N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfone group

ABSTRACT

The present invention relates to N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfone group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

The present invention relates to N-(pyridin-2-yl)pyrimidin-4-aminederivatives containing a sulfone group of general formula (I) asdescribed and defined herein, and methods for their preparation, theiruse for the treatment and/or prophylaxis of disorders, in particular ofhyper-proliferative disorders and/or virally induced infectious diseasesand/or of cardiovascular diseases. The invention further relates tointermediate compounds useful in the preparation of said compounds ofgeneral formula (I).

The family of cyclin-dependent kinase (CDK) proteins consists of membersthat are key regulators of the cell division cycle (cell cycle CDK's),that are involved in regulation of gene transcription (transcriptionalCDK's), and of members with other functions. CDKs require for activationthe association with a regulatory cyclin subunit. The cell cycle CDKsCDK1/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, andCDK6/cyclinD get activated in a sequential order to drive a cell intoand through the cell division cycle. The transcriptional CDKsCDK9/cyclin T and CDK7/cyclin H regulate the activity of RNApolymeraseII via phosphorylation of the carboxy-terminal domain (CTD). Positivetranscription factor b (P-TEFb) is a heterodimer of CDK9 and one of fourcyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b.

Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved intranscriptional regulation, CDK7 in addition participates in cell cycleregulation as CDK-activating kinase (CAK). Transcription of genes by RNApolymerase II is initiated by assembly of the pre-initiation complex atthe promoter region and phosphorylation of Ser 5 and Ser 7 of the CTD byCDK7/cyclin H. For a major fraction of genes RNA polymerase II stopsmRNA transcription after it moved 20-40 nucleotides along the DNAtemplate. This promoter-proximal pausing of RNA polymerase II ismediated by negative elongation factors and is recognized as a majorcontrol mechanism to regulate expression of rapidly induced genes inresponse to a variety of stimuli (Cho et al., Cell Cycle 9, 1697, 2010).P-TEFb is crucially involved in overcoming promoter-proximal pausing ofRNA polymerase II and transition into a productive elongation state byphosphorylation of Ser 2 of the CTD as well as by phosphorylation andinactivation of negative elongation factors.

Activity of P-TEFb itself is regulated by several mechanisms. About halfof cellular P-TEFb exists in an inactive complex with 7SK small nuclearRNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylenebis-acetamide inducible proteins 1/2 (HEXIMI/2, He et al., Mol Cell 29,588, 2008). The remaining half of P-TEFb exists in an active complexcontaining the bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535,2005). Brd4 recruits P-TEFb through interaction with acetylated histonesto chromatin areas primed for gene transcription. Through alternatelyinteracting with its positive and negative regulators, P-TEFb ismaintained in a functional equilibrium: P-TEFb bound to the 7SK snRNAcomplex represents a reservoir from which active P-TEFb can be releasedon demand of cellular transcription and cell proliferation (Zhou & Yik,Microbiol Mol Biol Rev 70, 646, 2006). Furthermore, the activity ofP-TEFb is regulated by posttranslational modifications includingphosphorylation/de-phosphorylation, ubiquitination, and acteylation(reviewed in Cho et al., Cell Cycle 9, 1697, 2010).

Deregulated activity of CDK9 kinase activity of the P-TEFb heterodimeris associated with a variety of human pathological settings such ashyper-proliferative diseases (e.g. cancer), virally induced infectiousdiseases or cardiovascular diseases:

Cancer is regarded as a hyper-proliferative disorder mediated by adisbalance of proliferation and cell death (apoptosis). High levels ofanti-apoptotic Bcl-2-family proteins are found in various human tumorsand account for prolonged survival of tumor cells and therapyresistance. Inhibition of P-TEFb kinase activity was shown to reducetranscriptional activity of RNA polymerase II leading to a decline ofshort-lived anti-apoptotic proteins, especially Mcl-1 and XIAP,reinstalling the ability of tumor cells to undergo apoptosis. A numberof other proteins associated with the transformed tumor phenotype (suchas Myc, NF-kB responsive gene transcripts, mitotic kinases) are eithershort-lived proteins or are encoded by short-lived transcripts which aresensitive to reduced RNA polymerase II activity mediated by P-TEFbinhibition (reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302,2008).

Many viruses rely on the transcriptional machinery of the host cell forthe transcription of their own genome. In case of HIV-1, RNA polymeraseII gets recruited to the promoter region within the viral LTRs. Theviral transcription activator (Tat) protein binds to nascent viraltranscripts and overcomes promoter-proximal RNA polymerase II pausing byrecruitment of P-TEFb which in turn promotes transcriptional elongation.Furthermore, the Tat protein increases the fraction of active P-TEFb byreplacement of the P-TEFb inhibitory proteins HEXIMI/2 within the 7SKsnRNA complex. Recent data have shown that inhibition of the kinaseactivity of P-TEFb is sufficient to block HIV-1 repliction at kinaseinhibitor concentrations that are not cytotoxic to the host cells(reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008).Similarly, recruitment of P-TEFb by viral proteins has been reported forother viruses such as B-cell cancer-associated Epstein-Barr virus, wherethe nuclear antigen EBNA2 protein interacts with P-TEFb (Bark-Jones etal., Oncogene, 25, 1775, 2006), and the human T-lymphotropic virus type1 (HTLV-1), where the transcriptional activator Tax recruits P-TEFb(Zhou et al., J Virol. 80, 4781, 2006).

Cardiac hypertrophy, the heart's adaptive response to mechanicaloverload and pressure (hemodynamic stress e.g. hypertension, myocardialinfarction), can lead, on a long term, to heart failure and death.Cardiac hypertrophy was shown to be associated with increasedtranscriptional activity and RNA polymerase II CTD phosphorylation incardiac muscle cells. P-TEFb was found to be activated by dissociationfrom the inactive 7SK snRNA/HEXIM1/2 complex. These findings suggestpharmacological inhibition of P-TEFb kinase activity as a therapeuticapproach to treat cardiac hypertrophy (reviewed in Dey et al., CellCycle 6, 1856, 2007).

In summary, multiple lines of evidence suggest that selective inhibitionof the CDK9 kinase activity of the P-TEFb heterodimer (=CDK9 and one offour cyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b) representsan innovative approach for the treatment of diseases such as cancer,viral diseases, and/or diseases of the heart. CDK9 belongs to a familyof at least 13 closely related kinases of which the subgroup of the cellcycle CDK's fulfills multiple roles in regulation of cell proliferation.Thus, co-inhibition of cell cycle CDKs (e.g. CDK1/cyclin B, CDK2/cyclinA, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9, is expected toimpact normal proliferating tissues such as intestinal mucosa, lymphaticand hematopoietic organs, and reproductive organs. To maximize thetherapeutic margin of CDK9 kinase inhibitors, molecules with highselectivity towards CDK9 are required.

CDK inhibitors in general as well as CDK9 inhibitors are described in anumber of different publications:

-   WO2008129070 and WO2008129071 both describe 2,4 disubstituted    aminopyrimidines as CDK inhibitors in general. It is also asserted    that some of these compounds may act as selective CDK9 inhibitors    (WO2008129070) and as CDK5 inhibitors (WO2008129071), respectively,    but no specific CDK9 IC₅₀ (WO2008129070) or CDK5 IC₅₀ (WO2008129071)    data is presented. These compounds do not contain a fluoro atom in    5-position of the pyrimidine core.-   WO2008129080 discloses 4,6 disubstituted aminopyrimidines and    demonstrates that these compounds show an inhibitory effect on the    protein kinase activity of various protein kinases, such as CDK1,    CDK2, CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9    inhibition (example 80).-   WO2005026129 discloses 4,6 disubstituted aminopyrimidines and    demonstrates that these compounds show an inhibitory effect on the    protein kinase activity of various protein kinases, in particular    CDK2, CDK4, and CDK9.-   WO2011116951 discloses substituted triazine derivatives as selective    CDK9 inhibitors.-   WO2012117048 discloses disubstituted triazine derivatives as    selective CDK9 inhibitors.-   WO2012117059 discloses disubstituted pyridine derivatives as    selective CDK9 inhibitors.-   EP1218360 B1, which corresponds to US2004116388A1, US7074789B2 and    W02001025220A1, describes triazine derivatives as kinase inhibitors,    but does not disclose potent or selective CDK9 inhibitors.-   WO2008079933 discloses aminopyridine and aminopyrimidine derivatives    and their use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or    CDK9 inhibitors.-   WO2011012661 describes aminopyridine derivatives useful as CDK    inhibitors.-   WO2011026917 discloses carboxamides derived from substituted    4-phenylpyridine-2-amines as inhibitors of CDK9.-   WO2012066065 discloses phenyl-heteroaryl amines as inhibitors of    CDK9. A selectivity towards CDK9 over other CDK isoforms is    preferred, however disclosure of CDK-inhibition data is confined to    CDK 9. No bicyclic ring systems are disclosed attached to the C4    position of the pyrimidine core. Within the group attached to C4 of    the pyrimidine core, alkoxy phenyls can be regarded as encompassed,    but there is no suggestion for a specific substitution pattern    characterised by a fluoro atom attached to C5 of the pyrimidine    ring, and an aniline at C2 of the pyrimidine, featuring a    substituted sulfonyl-methylene group in meta position. Compounds    shown in the examples typically feature a substituted cycloalkyl    group as R¹ but no phenyl.-   WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as    inhibitors of CDK9. The biaryl core mandatorily consists of two    heteroaromatic rings.-   WO2012101062 discloses substituted bi-heteroaryl compounds featuring    a 2-aminopyridine core as inhibitors of CDK9. The biaryl core    mandatorily consists of two heteroaromatic rings.-   WO2012101063 discloses carboxamides derived from substituted    4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.-   WO 2012101064 discloses N-acyl pyrimidine biaryl compounds as    inhibitors of CDK9.-   WO 2012101065 discloses pyrimidine biaryl compounds as inhibitors of    CDK9. The biaryl core mandatorily consists of two heteroaromatic    rings.-   WO 2012101066 discloses pyrimidine biaryl compounds as inhibitors of    CDK9. Substitution R¹ of the amino group attached to the    heteroaromatic core is confined to non-aromatic groups but does not    cover substituted phenyls. Furthermore, the biaryl core mandatorily    consists of two heteroaromatic rings.-   WO 2013037896 discloses disubstituted 5-fluoropyrimidines as    selective inhibitors of CDK9.-   WO 2013037894 discloses disubstituted 5-fluoropyromidine derivatives    containing a sulfoximine group as selective inhibitors of CDK9.-   Wang et al. (Chemistry & Biology 17, 1111-1121, 2010) describe    2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors,    which show anticancer activity in animal models.-   WO2004009562 discloses substituted triazine kinase inhibitors. For    selected compounds CDK1 and CDK4 test data, but no CDK9 data is    presented.

WO2004072063 describes heteroaryl (pyrimidine, triazine) substitutedpyrroles as inhibitors of protein kinases such as ERK2, GSK3, PKA orCDK2.

-   WO2010009155 discloses triazine and pyrimidine derivatives as    inhibitors of histone deacetylase and/or cyclin dependent kinases    (CDKs). For selected compounds CDK2 test data is described.-   WO2003037346 (corresponding to US7618968B2, US7291616B2,    US2008064700A1, US2003153570A1) relates to aryl triazines and uses    thereof, including to inhibit lysophosphatidic acid acyltransferase    beta (LPAAT-beta) activity and/or proliferation of cells such as    tumor cells.-   WO2008025556 describes carbamoyl sulfoximides having a pyrimidine    core, which are useful as kinase inhibitors. No CDK9 data is    presented. No molecules are exemplified, which possess a    fluoropyrimidine core.-   WO2002066481 describes pyrimidine derivatives as cyclin dependent    kinase inhibitors. CDK9 is not mentioned and no CDK9 data is    presented.-   WO2008109943 concerns phenyl aminopyri(mi)dine compounds and their    use as kinase inhibitors, in particular as JAK2 kinase inhibitors.    The specific examples mainly focus on compounds having a pyrimidine    core.-   WO2009032861 describes substituted pyrimidinyl amines as JNK kinase    inhibitors. The specific examples mainly focus on compounds having a    pyrimidine core.-   WO2011046970 concerns amino-pyrimidine compounds as inhibitors of    TBKL and/or IKK epsilon. The specific examples mainly focus on    compounds having a pyrimidine core.

Despite the fact that various inhibitors of CDKs are known, thereremains a need for selective CDK9 inhibitors to be used for thetreatment of diseases such as hyper-proliferative diseases, viraldiseases, and/or diseases of the heart, which offer one or moreadvantages over the compounds known from prior art, such as:

improved activity and/or efficacy

-   -   beneficial kinase selectivity profile according to the        respective therapeutic need    -   improved side effect profile, such as fewer undesired side        effects, lower intensity of side effects, or reduced        (cyto)toxicity    -   improved physicochemical properties, such as solubility in water        and body fluids    -   improved pharmacokinetic properties, allowing e.g. for dose        reduction or an easier dosing scheme    -   easier drug substance manufacturing e.g. by shorter synthetic        routes or easier purification.

A particular object of the invention is to provide CDK9 kinaseinhibitors which, compared to the compounds known from prior art, showan increased selectivity for CDK9/Cyclin T1 as compared to CDK2/CyclinE.

Another object of the invention is to provide CDK9 kinase inhibitorswhich show an increased potency to inhibit CDK9 activity (demonstratedby a lower 1050 value for CDK9/Cyclin T1) compared to the compoundsknown from prior art.

Another object of the invention is to provide CDK9 kinase inhibitorswhich show an increased potency to inhibit CDK9 activity at high ATPconcentrations compared to the compounds known from prior art.

Another object of the invention is to provide CDK9 kinase inhibitors,which show an improved anti-proliferative activity in tumor cell linessuch as HeLa compared to the compounds known from prior art.

Further, it is also an object of the present invention to provide CDK9kinase inhibitors, which, compared to the compounds known from priorart, are highly selective for CDK9/Cyclin T1 as compared to CDK2/CyclinE, and/or which show an increased potency to inhibit CDK9 activityand/or which show an improved anti-proliferative activity in tumor celllines such as HeLa and/or which show an increased potency to inhibitCDK9 activity at high ATP concentrations compared to the compounds knownfrom prior art.

The present invention relates to compounds of general formula (I)

wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-,    heterocyclyl-, phenyl, heteroaryl, phenyl-C₁-C₃-alkyl- or    heteroaryl-C₁-C₃-alkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy, cyano, halogen, halo-C₁-C₃-alkyl-,        C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, —OP(O)(OH)₂, —C(O)OH, —C(O)NH₂;-   R² represents a group selected from

-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, bromo atom, cyano,    C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁵ represents a group selected from    -   a) a C₁-C₆-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-,        C₂-C₃-alkynyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl,        heteroaryl, wherein said C₃-C₇-cycloalkyl-, heterocyclyl-,        phenyl or heteroaryl group is optionally substituted with one,        two or three substituents, identically or differently, selected        from halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   b) a C₃-C₇-cycloalkyl- group, which is optionally substituted        with one or two or three substituents, identically or        differently, selected from the group of halogen, hydroxy, —NH₂,        alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-,        C₂-C₃-alkenyl-, C₂-C₃-alkynyl-;    -   c) a heterocyclyl-group, which is optionally substituted with        one or two or three substituents, identically or differently,        selected from the group of halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-,        C₂-C₃-alkynyl-;    -   d) a phenyl group, which is optionally substituted with one or        two or three substituents, identically or differently, selected        from the group of halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   e) a heteroaryl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from the group of halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   f) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   g) a heteroaryl-C₁-C₃-alkyl-group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   h) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl-group, which C₃-C₆-cycloalkyl        group is optionally substituted with one or two or three        substituents, identically or differently, selected from halogen,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   i) a heterocyclyl-C₁-C₃-alkyl-group, which heterocyclyl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from halogen, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    or their salts, solvates or salts of solvates.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds of the hereinafter recited formula which are encompassed byformula (I) and the salts, solvates and solvates of the salts thereof,and the compounds which are encompassed by formula (I) and are mentionedhereinafter as exemplary embodiments and the salts, solvates andsolvates of the salts thereof, where the compounds which are encompassedby formula (I) and are mentioned hereinafter are not already salts,solvates and solvates of the salts.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The invention therefore relates to the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated in a known manner from such mixtures of enantiomersand/or diastereomers.

If the compounds according to the invention can be in tautomeric forms,the present invention encompasses all tautomeric forms.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any physiologically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

Salts which are preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. However, salts which are not suitable for pharmaceuticalapplications per se, but which, for example, can be used for theisolation or purification of the compounds according to the invention,are also comprised.

The term “physiologically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention, for example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

Physiologically acceptable salts of the compounds according to theinvention encompass acid addition salts of mineral acids, carboxylicacids and sulfonic acids, for example salts of hydrochloric acid,hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, phosphoricacid, nitric acid or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Physiologically acceptable salts of the compounds according to theinvention also comprise salts of conventional bases, such as, by way ofexample and by preference, alkali metal salts (for example sodium andpotassium salts), alkaline earth metal salts (for example calcium andmagnesium salts) and ammonium salts derived from ammonia or organicamines with 1 to 16 C atoms, such as, by way of example and bypreference, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidine, N-methylglucamine, dimethylglucamine,ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol,tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol. Additionally, basic nitrogen containinggroups may be quaternised with such agents as lower alkylhalides such asmethyl-, ethyl-, propyl-, and butylchlorides, -bromides and -iodides;dialkylsulfates like dimethyl-, diethyl-, dibutyl- and diamylsulfates,long chain halides such as decyl-, lauryl-, myristyl-andstearylchlorides, -bromides and -iodides, aralkylhalides like benzyl-and phenethylbromides and others. Additionally, the compounds accordingto the invention may form salts with a quarternary ammonium ionobtainable e.g. by quarternisation of a basic nitrogen containing groupwith agents like lower alkylhalides such as methyl-, ethyl-, propyl-,and butylchlorides, -bromides and -iodides; dialkylsulfates likedimethyl-, diethyl-, dibutyl- and diamylsulfates, long chain halidessuch as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and-iodides, aralkylhalides like benzyl- and phenethylbromides and others.Examples of suitable quarternary ammonium ions are tetramethylammonium,tetraethylammonium, tetra(n-propyl)ammonium, tetra (n-butyl)ammonium, orN-benzyl-N,N,N-trimethylammonium.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds according to the invention which form a complexwith solvent molecules by coordination in the solid or liquid state.Hydrates are a special form of solvates in which the coordination takesplace with water. Hydrates are preferred as solvates within the scope ofthe present invention.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

In addition, the present invention also encompasses prodrugs of thecompounds according to the invention. The term “prodrugs” encompassescompounds which themselves may be biologically active or inactive, butare converted (for example by metabolism or hydrolysis) to compoundsaccording to the invention during their residence time in the body.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

Accordingly, the present invention includes all possible salts,polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters)thereof, and diastereoisomeric forms of the the compounds of the presentinvention as single salt, polymorph, metabolite, hydrate, solvate,prodrug (e.g.: esters) thereof, or diastereoisomeric form, or as mixtureof more than one salt, polymorph, metabolite, hydrate, solvate, prodrug(e.g.: esters) thereof, or diastereoisomeric form in any ratio.

For the purposes of the present invention, the substituents have thefollowing meaning, unless otherwise specified:

The terms “halogen”, “halogen atom” or “halo” represent fluorine,chlorine, bromine and iodine, particularly chlorine or fluorine,preferably fluorine.

The term “alkyl” represents a linear or branched alkyl radical havingthe number of carbon atoms specifically indicated, e.g. C₁-C₁₀ to one,two, three, four, five, six, seven, eight, nine or ten carbon atoms,e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl-, decyl-,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl. If thenumber of carbon atoms is not specifically indicated the term “alkyl”represents a linear or branched alkyl radical having, as a rule, 1 to 9,particularly 1 to 6, preferably 1 to 4 carbon atoms. Particularly, thealkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms (“C₁-C₆-alkyl”), e.g.methyl, ethyl, n-propyl-, isopropyl, n-butyl, tert-butyl, pentyl,isopentyl, hexyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl,1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl,3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl,1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl. Preferably,the alkyl group has 1, 2 or 3 carbon atoms (“C₁-C₃-alkyl”), methyl,ethyl, n-propyl or isopropyl.

The term “C₂-C₃-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains onedouble bond, and which has 2 or 3 carbon atoms (“C₂-C₃-alkenyl”). Saidalkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl,(Z)-2-methylvinyl or isopropenyl group.

The term “C₂-C₃-alkynyl” is to be understood as preferably meaning alinear, monovalent hydrocarbon group which contains one triple bond, andwhich contains 2 or 3 carbon atoms. Said C₂-C₃-alkynyl group is, forexample, ethynyl, prop-1-ynyl or prop-2-ynyl group.

The term “C₃-C₇-cycloalkyl” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4,5, 6 or 7 carbon atoms. Said C₃-C₇-cycloalkyl group is for example, amonocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl group. Said cycloalkyl ring canoptionally contain one or more double bonds e.g. cycloalkenyl, such as acyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl orcycloheptenyl group, wherein the bond between said ring with the rest ofthe molecule may be to any carbon atom of said ring, be it saturated orunsaturated. Particularly, said cycloalkyl group is a C₄-C₆-cycloalkyl,a C₅-C₆-cycloalkyl or a cyclohexyl group.

The term “C₃-C₅-cycloalkyl” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4or 5 carbon atoms. In particular said C₃-C₅-cycloalkyl group is amonocyclic hydrocarbon ring such as a cyclopropyl, cyclobutyl orcyclopentyl group. Preferably said “C₃-C₅-cycloalkyl” group is acyclopropyl group.

The term “C₃-C₆-cycloalkyl” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4,5 or 6 carbon atoms. In particular said C₃-C₅-cycloalkyl group is amonocyclic hydrocarbon ring such as a cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl group.

The term “C₃-C₆-cycloalkyl-C₁-C₃-alkyl-” group is to be understood aspreferably meaning a C₃-C₆-cycloalkyl group as defined supra, in whichone of the hydrogen atoms is replaced by a C₁-C₃-alkyl group, as definedsupra, that links the C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group to themolecule. Particularly, the “C₃-C₆-cycloalkyl-C₁-C₃-alkyl-” is a“C₃-C₆-cycloalkyl-C₁-C₂-alkyl-”, preferably it is a“C₃-C₆-cycloalkyl-methyl-” group.

The term “heterocyclyl” is to be understood as meaning a saturated orpartially unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and further containing1, 2 or 3 heteroatom-containing groups selected from oxygen, sulfur,nitrogen. Particularly, the term “heterocyclyl” is to be understood asmeaning a “4- to 10-membered heterocyclic ring”.

The term “a 4- to 10-membered heterocyclic ring” is to be understood asmeaning a saturated or partially unsaturated, monovalent, mono- orbicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbonatoms, and further containing 1, 2 or 3 heteroatom-containing groupsselected from oxygen, sulfur, nitrogen. A C₃-C₉-heterocyclyl is to beunderstood as meaning a heterocyclyl which contains at least 3, 4, 5, 6,7, 8 or 9 carbon atoms and additionally at least one heteroatom as ringatoms. Accordingly in case of one heteroatom the ring is 4- to10-membered, in case of two heteroatoms the ring is 5- to 11-memberedand in case of three heteroatoms the ring is 6- to 12-membered.

Said heterocyclic ring is for example, a monocyclic heterocyclic ringsuch as an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, 1,4-dioxanyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, morpholinyl, 1,3-dithianyl, thiomorpholinyl, piperazinyl,or chinuclidinyl group. Optionally, said heterocyciclic ring can containone or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl,2,5-dihydro-1H-pyrrolyl, 1,3-dioxolyl, 4H-1,3,4-thiadiazinyl,2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl,2,3-dihydrothienyl, dihydrooxazolyl, 4,5-dihydroisoxazolyl, or4H-1,4-thiazinyl group, or, it may be benzo fused.

Particularly a C₃-C₇-heterocyclyl is to be understood as meaning aheterocyclyl which contains at least 3, 4, 5, 6, or 7 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 8-membered, in case of twoheteroatoms the ring is 5- to 9-membered and in case of threeheteroatoms the ring is 6- to 10-membered.

Particularly a C₃-C₆-heterocyclyl is to be understood as meaning aheterocyclyl which contains at least 3, 4, 5 or 6 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 7-membered, in case of twoheteroatoms the ring is 5- to 8-membered and in case of threeheteroatoms the ring is 6- to 9-membered.

Particularly, the term “heterocyclyl” is to be understood as being aheterocyclic ring which contains 3, 4 or 5 carbon atoms, and 1, 2 or 3of the above-mentioned heteroatom-containing groups (a “4- to 7-memberedheterocyclic ring”), more particularly said ring can contain 4 or 5carbon atoms, and 1, 2 or 3 of the above-mentioned heteroatom-containinggroups (a “5- to 7-membered heterocyclic ring”), more particularly saidheterocyclic ring is a “6-membered heterocyclic ring”, which is to beunderstood as containing 4 carbon atoms and 2 of the above-mentionedheteroatom-containing groups or 5 carbon atoms and one of theabove-mentioned heteroatom-containing groups, preferably 4 carbon atomsand 2 of the above-mentioned heteroatom-containing groups.

The term “heterocyclyl-C₁-C₃-alkyl-” group is to be understood aspreferably meaning a heterocyclyl, preferably a 4- to 7-memberedheterocyclic ring, more preferably a 5- to 7-membered heterocyclic ring,each as defined supra, in which one of the hydrogen atoms is replaced bya C₁-C₃-alkyl group, as defined supra, that links theheterocyclyl-C₁-C₃-alkyl- group to the molecule. Particularly, the“heterocyclyl-C₁-C₃-alkyl-” is a “heterocyclyl-C₁-C₂-alkyl-”, preferablyit is a heterocyclyl-methyl-group.

The term “C₁-C₆-alkoxy-” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentyloxy, iso-pentyloxy, n-hexyloxy group, or an isomerthereof. Particularly, the “C₁-C₆-alkoxy-” group is a “C₁-C₄-alkoxy-”, a“C₁-C₃-alkoxy-”, a methoxy, ethoxy, or propoxy group, preferably amethoxy, ethoxy or propoxy group. Further preferred is a “C₁-C₂-alkoxy-”group, particularly a methoxy or ethoxy group.

The term “C₁-C₃-fluoroalkoxy-” is to be understood as preferably meaninga linear or branched, saturated, monovalent, C₁-C₃-alkoxy-group, asdefined supra, in which one or more of the hydrogen atoms is replaced,identically or differently, by one or more fluoro atoms. SaidC₁-C₃-fluoroalkoxy-group is, for example a 1,1-difluoromethoxy-, a1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-, a 3-fluoropropoxy-, a2,2,2-trifluoroethoxy-, a 3,3,3-trifluoropropoxy-particularly a“C₁-C₂-fluoroalkoxy-” group.

The term “alkylamino-” is to be understood as preferably meaning analkylamino group with one linear or branched alkyl group as definedsupra. (C₁-C₃)-alkylamino- for example means a monoalkylamino group with1, 2 oder 3 carbon atoms, (C₁-C₆)-alkylamino- with 1, 2, 3, 4, 5 or 6carbon atoms. The term “alkylamino-” comprises for example methylamino-,ethylamino-, n-propylamino-, isopropylamino-, tert.-butylamino-,n-pentylamino- or n-hexylamino-.

The term “dialkylamino-” is to be understood as preferably meaning analkylamino group having two linear or branched alkyl groups as definedsupra, which are independent from each other. (C₁-C₃)-dialkylamino- forexample represents a dialkylamino group with two alkyl groups each ofthem having 1 to 3 carbon atoms per alkyl group. The term“dialkylamino-” comprises for example: N,N-Dimethylamino-,N,N-Diethylamino-, N-Ethyl-N-methylamino-, N-Methyl-N-n-propylamino-,N-Isopropyl-N-n-propylamino-, N-t-Butyl-N-methylamino-,N-Ethyl-N-n-pentylamino- and N-n-Hexyl-N-methylamino-.

The term “cyclic amine” is to be understood as preferably meaning acyclic amine group. Preferably, a cyclic amine means a saturated,monocyclic group with 4 to 10, preferably 4 to 7 ring atoms of which atleast one ring atom is a nitrogen atom. Suitable cyclic amines areespecially azetidine, pyrrolidine, piperidine, piperazine,1-methylpiperazine, morpholine, thiomorpholine, which could beoptionally substituted by one or two methyl groups.

The term “halo-C₁-C₃-alkyl-” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₃-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is fluorine. Preferred halo-C₁-C₃-alkyl- group is afluoro-C₁-C₃-alkyl- group, such as for example —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, or —CH₂CF₃, preferably it is —CF₃.

The term “phenyl-C₁-C₃-alkyl-” is to be understood as preferably meaninga phenyl group, in which one of the hydrogen atoms is replaced by aC₁-C₃-alkyl group, as defined supra, that links the phenyl-C₁-C₃-alkyl-group to the molecule. Particularly, the “phenyl-C₁-C₃-alkyl-” is aphenyl-C₁-C₂-alkyl-, preferably it is a benzyl-group.

The term “heteroaryl” is to be understood as preferably meaning amonovalent, aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5(a “5-membered heteroaryl”) or 6 (a “6-membered heteroaryl”) or 9 (a“9-membered heteroaryl”) or 10 ring atoms (a “10-membered heteroaryl”),and which contains at least one heteroatom which may be identical ordifferent, said heteroatom being such as oxygen, nitrogen or sulfur, andcan be monocyclic, bicyclic, or tricyclic, and in addition in each casecan be benzo-condensed. Particularly, heteroaryl is selected fromthienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,tetrazolyl etc., and benzo derivatives thereof, such as, for example,benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl,benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; orpyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzoderivatives thereof, such as, for example, quinolinyl, quinazolinyl,isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzoderivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.Preferably, heteroaryl is selected from monocyclic heteroaryl,5-membered heteroaryl or 6-membered heteroaryl.

The term “5-membered heteroaryl” is understood as preferably meaning amonovalent, aromatic ring system having 5 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“5-membered heteroaryl” is selected from thienyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.

The term “6-membered heteroaryl” is understood as preferably meaning amonovalent, aromatic ring system having 6 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“6-membered heteroaryl” is selected from pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl.

The term “heteroaryl-C₁-C₃-alkyl-” is to be understood as preferablymeaning a heteroaryl, a 5-membered heteroaryl or a 6-membered heteroarylgroup, each as defined supra, in which one of the hydrogen atoms isreplaced by a C₁-C₃-alkyl group, as defined supra, that links theheteroaryl-C₁-C₃-alkyl- group to the molecule. Particularly, the“heteroaryl-C₁-C₃-alkyl-” is a heteroaryl-C₁-C₂-alkyl-, apyridinyl-C₁-C₃-alkyl-, a pyridinylmethyl-, a pyridinylethyl-, apyridinylpropyl-, -a pyrimidinyl-C₁-C₃-alkyl-, a pyrimidinylmethyl-, apyrimidinylethyl-, a pyrimidinylpropyl-, preferably a pyridinylmethyl-or a pyridinylethyl- or a pyrimidinylethyl- or apyrimidinylpropyl-group.

As used herein, the term “leaving group” refers to an atom or a group ofatoms that is displaced in a chemical reaction as stable species takingwith it the bonding electrons. Preferably, a leaving group is selectedfrom the group comprising: halo, in particular chloro, bromo or iodo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy,(4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy,(4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy,benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy.

The term “C₁-C₁₀”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₁₀-alkyl” is to be understood as meaning an alkylgroup having a finite number of carbon atoms of 1 to 10, i.e. 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is to be understood further thatsaid term “C₁-C₁₀” is to be interpreted as any sub-range comprisedtherein, e.g. C₁-C₁₀, C₁-C₉, C₁-C₈, C₁-C₇, C₁-C₆ C₁-C₅, C₁-C₄, C₁-C₃,C₁-C₂, C₂-C₁₀, C₂-C₉, C₂-C₈, C₂-C₇, C₂-C₆, C₂-C₅, C₂-C₄, C₃-C₁₀, C₃-C₉,C₃-C₈, C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₁₀, C₄-C₉, C₄-C₈, C₄-C₇, C₄-C₆,C₄-C₅, C₅-C₁₀, C₅-C₉, C₅-C₈, C₅-C₇, C₅-C₆, C₆-C₁₀, C₆-C₉, C₆-C₈, C₆-C₇,C₇-C₁₀, C₇-C₉, C₇-C₈, C₈-C₁₀, C₈-C₉, C₉-C₁₀.

Similarly, as used herein, the term “C₁-C₆”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₆-alkyl-”,“C₁-C₆-alkoxy” is to be understood as meaning an alkyl group having afinite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbonatoms. It is to be understood further that said term “C₁-C₆” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₆ C₁-C₅, C₁C₄,C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆,C₄-C₅, C₅-C₆.

Similarly, as used herein, the term “C₁-C₃”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₃-alkyl”,“C₁-C₃-alkoxy-” or “C₁-C₃-fluoroalkoxy” is to be understood as meaningan alkyl group having a finite number of carbon atoms of 1 to 3, i.e. 1,2 or 3 carbon atoms. It is to be understood further that said term“C₁-C₃” is to be interpreted as any sub-range comprised therein, e.g.C₁-C₃, C₁-C₂, C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅,C₅-C₆.

Further, as used herein, the term “C₃-C₇”, as used throughout this text,e.g. in the context of the definition of “C₃-C₇-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms, particularly3, 4, 5 or 6 carbon atoms. It is to be understood further that said term“C₃-C₇” is to be interpreted as any sub-range comprised therein, e.g.C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₇, C₅-C₆, C₆-C₇.

A symbol

at a bond denotes the linkage site in the molecule.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning one, two, three, four or five times,particularly one, two, three or four times, more particularly one, twoor three times, even more particularly one or two times.

Where the plural form of the word compounds, salts, hydrates, solvatesand the like, is used herein, this is taken to mean also a singlecompound, salt, isomer, hydrate, solvate or the like.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₃-alkoxy-,        halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, -NH₂, —OP(O)(OH)₂,        —C(O)OH, —C(O)NH₂;-   R² represents a group selected from

-   R³ represents a hydrogen atom, a fluoro atom, a chloro atom,    C₁-C₃-alkyl or halo-C₁-C₃-alkyl-;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₆-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-,        C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, wherein        said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl        group is optionally substituted with one, two or three        substituents, identically or differently, selected from halogen,        hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,        cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   d) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, which C₃-C₆-cycloalkyl        group is optionally substituted with one or two or three        substituents, identically or differently, selected from halogen,        C₁-C₃-alkyl-, C₁-C₃-alkoxy, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   e) a heterocyclyl-C₁-C₃-alkyl- group, which heterocyclyl group        is optionally substituted with one or two or three substituents,        identically or differently, selected from halogen, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₂-alkoxy-,        halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, —NH₂, —OP(O)(OH)₂,        —C(O)OH, —C(O)NH₂;-   R² represents a group selected from

-   R³ represents a hydrogen atom, a fluoro atom or a chloro atom;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R³ represents a group selected from    -   a) a C₁-C₆-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-,        C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, wherein        said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl        group is optionally substituted with one, two or three        substituents, identically or differently, selected from halogen,        hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,        cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   d) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, which C₃-C₆-cycloalkyl        group is optionally substituted with one or two or three        substituents, identically or differently, selected from halogen,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   e) a heterocyclyl-C₁-C₃-alkyl- group, which heterocyclyl group        is optionally substituted with one or two or three substituents,        identically or differently, selected from halogen, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₇-cycloalkyl    or phenyl-C₁-C₃-alkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy or C₁-C₆-alkoxy,-   R² represents a group selected from

-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen or fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₆-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-,        C₂-C₃-alkynyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl,        heteroaryl, wherein said C₃-C₇-cycloalkyl-, heterocyclyl-,        phenyl or heteroaryl group is optionally substituted with one,        two or three substituents, identically or differently, selected        from halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃ alkyl,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    wherein said group is optionally substituted with one or two    substituents, identically or differently, selected from the group of    hydroxy, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-;-   R² represents a group selected from

-   R³ represents a hydrogen atom or a fluoro atom;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₆-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-,        C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, wherein        said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl        group is optionally substituted with one, two or three        substituents, identically or differently, selected from halogen,        hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,        cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   d) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, which C₃-C₆-cycloalkyl        group is optionally substituted with one or two or three        substituents, identically or differently, selected from halogen,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   e) a heterocyclyl-C₁-C₃-alkyl- group, which heterocyclyl group        is optionally substituted with one or two or three substituents,        identically or differently, selected from halogen, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₄-alkyl-, C₃-C₆-cycloalkyl    or phenyl-C₁-C₂-alkyl-, wherein said group is optionally substituted    with one or two or three substituents, identically or differently,    selected from the group of hydroxy or C₁-C₃-alkoxy,-   R² represents a group selected from

-   R³, R⁴ represent, independently from each other a group selected    from a hydrogen or fluoro atom,-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, hydroxy, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-,        C₂-C₃-alkynyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl,        heteroaryl, wherein said C₃-C₇-cycloalkyl-, heterocyclyl-,        phenyl or heteroaryl group is optionally substituted with one,        two or three substituents, identically or differently, selected        from halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, hydroxy,        —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen,        hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen or fluoro atom or C₁-C₃-alkoxy-,    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a C₁-C₆-alkyl group,    -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₃-alkoxy-,        —NH₂, —OP(O)(OH)₂;-   R² represents a group selected from

-   R³ represents a hydrogen atom, fluoro atom, C₁-C₂-alkyl or    fluoro-C₁-C₂-alkyl-;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, halo-C₁-C₃-alkyl-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, a fluoro atom or a chloro atom;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a C₁-C₆-alkyl group,    -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₆-alkoxy-,        —NH₂, —OP(O)(OH)₂;-   R² represents a group selected from

-   R³ represents a hydrogen atom, fluoro atom or chloro atom;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, halo-C₁-C₃-alkyl-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, a fluoro atom or a chloro atom;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    wherein said group is optionally substituted with one or two    substituents, identically or differently, selected from the group of    hydroxy, C₁-C₆-alkoxy-;-   R² represents a group selected from

-   R³ represents a hydrogen atom or fluoro atom;-   R⁴ represents a hydrogen atom or a fluoro atom;-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group, which is optionally substituted with one        or two or three substituents, identically or differently,        selected from halogen, cyano, halo-C₁-C₃-alkyl-;    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;    -   c) a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two substituents, identically        or differently, selected from the group of halogen, cyano,        C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,        C₁-C₃-alkoxy-;    -   d) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, which C₃-C₆-cycloalkyl        group is optionally substituted with one or two or three        substituents, identically or differently, selected from halogen,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-;    -   e) a heterocyclyl-C₁-C₃-alkyl- group, which heterocyclyl group        is optionally substituted with one or two or three substituents,        identically or differently, selected from halogen, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom or a fluoro atom;    or their salts, solvates or salts of solvates.

In a preferred embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a C₁-C₆-alkyl group,    -   wherein said group is optionally substituted with one        substituent, selected from the group of hydroxy or —OP(O)(OH)₂;-   R² represents the group

-   R³ represents a hydrogen atom, fluoro atom, C₁-C₂-alkyl or    fluoro-C₁-C₂-alkyl-;-   R⁴ represents a hydrogen atom;-   R⁵ represents a C₁-C₃-alkyl group;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom or a fluoro atom;    or their salts, solvates or salts of solvates.

In a preferred embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a C₁-C₆-alkyl group,    -   wherein said group is optionally substituted with one        substituent, selected from the group of hydroxy or —OP(O)(OH)₂;-   R² represents a group selected from

-   R³ represents a hydrogen atom or chloro atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a C₁-C₃-alkyl group;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, fluoro atom or chloro atom;-   or their salts, solvates or salts of solvates

In another preferred embodiment the present invention concerns compoundsof general formula (I), wherein

-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group of hydroxy, C₁-C₆-alkoxy-;-   R² represents a group selected from

-   R³ represents a hydrogen atom or fluoro atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group;    -   b) a phenyl-C₁-C₃-alkyl- group;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom or fluoro atom; or their salts, solvates or    salts of solvates.

In another preferred embodiment the present invention concerns compoundsof general formula (I),

-   R¹ represents a group selected from C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-    or phenyl-C₁-C₂-alkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy or methoxy,-   R² represents a group selected from

-   R³ represents a hydrogen or fluoro atom,-   R⁴ represents a hydrogen atom,-   R⁵ represents a group selected from    -   a) a C₁-C₃-alkyl group,    -   b) a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionally        substituted with one or two or three substituents, identically        or differently, selected from the group of halogen or        C₁-C₃-alkoxy-,    -   c) a pyridyl-C₁-C₃-alkyl- group, which heteroaryl group is        optionally substituted with one or two or three substituents,        identically or differently, selected from the group of halogen        or C₁-C₃-alkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen or fluoro atom,    or their salts, solvates or salts of solvates.

In another preferred embodiment the present invention concerns compoundsof general formula (I), wherein

-   R¹ represents a C₁-C₃-alkyl group;-   R² represents the group

-   R³ represents a hydrogen atom, a fluoro atom, a methyl or a    trifluoromethyl group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a C₁-C₃-alkyl group;-   R⁶ represents fluoro;-   R⁷ represents hydrogen;    or their salts, solvates or salts of solvates.

In another preferred embodiment the present invention concerns compoundsof general formula (I), wherein

-   R¹ represents a C₁-C₃-alkyl group;-   R² represents a group

-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a C₁-C₃-alkyl group;-   R⁶ represents hydrogen, para-fluoro, or para-chloro, whereby para    refers to the point of attachment of R² to the rest of the molecule;-   R⁷ represents hydrogen;    or their salts, solvates or salts of solvates.

In another preferred embodiment the present invention concerns compoundsof general formula (I), wherein

-   R¹ represents a group selected from methyl, ethyl, propan-2yl-,    cyclopropyl, tert-butyl-, cyclohexyl,    -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, methoxy-;        C₁-C₆-alkoxy-;-   R² represents a group selected from

-   R³ represents a hydrogen atom or fluoro atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from methyl and benzyl;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom or fluoro atom;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a group selected from methyl, ethyl, propan-2yl-,    cyclopropyl, tert-butyl-, cyclohexyl, wherein said group is    optionally substituted with one substituent selected from the group    of hydroxy, methoxy-; C₁-C₆-alkoxy-;-   R² represents a group selected from 4-fluoro-2-methoxyphenyl-,    2-(benzyloxy)-4-fluorophenyl-, 3,4-dihydro-2H-chromen-8-yl-;-   R³ represents a hydrogen atom or fluoro atom;-   R⁴ represents a hydrogen atom;    or their salts, solvates or salts of solvates.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein

-   R¹ represents a methyl group;-   R² represents a group selected from 4-fluoro-2-methoxyphenyl-,    2-(benzyloxy)-4-fluorophenyl-, 3,4-dihydro-2H-chromen-8-yl-;-   R³ represents a hydrogen atom or fluoro atom;-   R⁴ represents a hydrogen atom;    or their salts, solvates or salts of solvates.

In a particularly preferred embodiment the present invention concernscompounds of general formula (I), wherein

-   R¹ represents a methyl group;-   R² represents a 4-fluoro-2-methoxyphenyl group;-   R³ represents a hydrogen atom, a fluoro atom, a methyl or    trifluoromethyl group;-   R⁴ represents a hydrogen atom;    or their salts, solvates or salts of solvates.

In a particularly preferred embodiment the present invention concernscompounds of general formula (I), wherein

-   R¹ represents a methyl group;-   R² represents a 4-fluoro-2-methoxyphenyl group;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;    or their salts, solvates or salts of solvates.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₆-alkyl-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,phenyl-C₁-C₃-alkyl- or heteroaryl-C₁-C₃-alkyl-,

-   -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy, cyano, halogen, halo-C₁-C₃-alkyl-,        C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, —OP(O)(OH)₂, —C(O)OH, —C(O)NH₂;

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a C₁-C₃-alkyl-, a C₃-C₅-cycloalkyl-, a 4- to7-membered heterocyclic ring, a phenyl, a heteroaryl, aphenyl-C₁-C₂-alkyl- or a heteroaryl-C₁-C₂-alkyl- group,

-   -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy, cyano, halogen, halo-C₁-C₂-alkyl-,        C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a phenyl or a heteroaryl group,

-   -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy, cyano, halogen, halo-C₁-C₂-alkyl-,        C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein R¹ represents a group selected fromC₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,

-   -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₃-alkoxy-,        halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, —NH₂, —OP(O)(OH)₂,        —C(O)OH, —C(O)NH₂.

In another embodiment the present invention concerns compounds ofgeneral formula (I), wherein R¹ represents a group selected fromC₁-C₆-alkyl-, C₃-C₅-cycloalkyl-,

-   -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group of hydroxy, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-,        C₁-C₂-fluoroalkoxy-, —NH₂, —OP(O)(OH)₂, —C(O)OH, —C(O)NH₂.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from methyl, ethyl, propan-2-yl,cyclopropyl, tert-butyl, cyclopentyl, cyclohexyl or phenyl;

-   -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxyl or methoxy.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from methyl, ethyl, propan-2-yl,tert butyl, cyclopropyl, cyclohexyl or phenyl,

-   -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxyl or methoxy.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₆-alkyl-,C₃-C₇-cycloalkyl or phenyl-C₁-C₃-alkyl-,

-   -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy or C₁-C₆-alkoxy.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₄-alkyl-,C₃-C₆-cycloalkyl or phenyl-C₁-C₂-alkyl-,

-   -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group of hydroxy or C₁-C₃-alkoxy.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a C₁-C₆-alkyl group,

-   -   wherein said group is optionally substituted with one        substituent, selected from the group of hydroxy, C₁-C₃-alkoxy-,        —NH₂, —OP(O)(OH)₂.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a C₁-C₆-alkyl group,

-   -   wherein said group is optionally substituted with one        substituent selected from the group of hydroxy, C₁-C₆-alkoxy-,        —NH₂, —OP(O)(OH)₂.

In a preferred embodiment the present invention concerns compounds ofgeneral formula (I), wherein R¹ represents a C₁-C₆-alkyl group,

-   -   wherein said group is optionally substituted with one        substituent, selected from the group of hydroxy or —OP(O)(OH)₂;

In another preferred embodiment the present invention concerns compoundsof general formula (I), wherein R¹ represents a C₁-C₃-alkyl group.

In a particularly preferred embodiment the present invention concernscompounds of general formula (I), wherein R¹ represents a methyl group.

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from

In a preferred embodiment the invention relates to compounds of formula(I), in which R² represents

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from 4-fluoro-2-methoxyphenyl-or 2-(benzyloxy)-4-fluorophenyl-.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a4-fluoro-2-methoxyphenyl-group.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, bromo atom, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluoro atom, a chloro atom,C₁-C₃-alkyl or halo-C₁-C₃-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents C₁-C₃-alkyl.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents halo-C₁-C₃-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluoro atom, a chloro atom,C₁-C₂-alkyl or fluoro-C₁-C₂-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents C₁-C₂-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents fluoro-C₁-C₂-alkyl-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a hydrogen atom, a fluoro atom, a methyl ora trifluoromethyl group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a methyl or a trifluoromethyl group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a trifluoromethyl group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a methyl group.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen, a fluoro or achloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom or chloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a fluoro or a chloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom or a fluoroatom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a fluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent independently from each other a groupselected from a hydrogen or fluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluoro atom, a chloro atom,C₁-C₃-alkyl or halo-C₁-C₃-alkyl- and R⁴ represents a hydrogen atom or afluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluoro atom, a chloro atom,C₁-C₂-alkyl or fluoro-C₁-C₂-alkyl- and R⁴ represents a hydrogen atom ora fluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluoro atom, a chloro atom,C₁-C₂-alkyl or fluoro-C₁-C₂-alkyl- and R⁴ represents a hydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a hydrogen atom, a fluoro atom, a methyl ora trifluoromethyl group, and R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen or fluoro atom and R⁴ represents ahydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁴ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁴ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁴ represents a group selected from a hydrogen, a fluoro or achloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁴ represents a fluoro or a chloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁴ represents a group selected from a hydrogen atom or fluoroatom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁴ represents a hydrogen atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁴ represents a fluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₆-alkyl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-,C₃-C₇-cycloalkyl-, C₃-C₇-heterocyclyl-, phenyl, heteroaryl,

-   -   wherein said C₃-C₇-cycloalkyl-, C₃-C₇-heterocyclyl-, phenyl or        heteroaryl group is optionally substituted with one, two or        three substituents, identically or differently, selected from        halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₆-alkyl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from halogen, hydroxy, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,

-   -   wherein said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or        heteroaryl group is optionally substituted with one, two or        three substituents, identically or differently, selected from        halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from halogen, hydroxy, —NH₂, alkylamino-,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-, C₃-C₇-cycloalkyl-,heterocyclyl-, phenyl, heteroaryl,

-   -   wherein said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or        heteroaryl group is optionally substituted with one, two or        three substituents, identically or differently, selected from        halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, alkylamino-,        dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic        amines, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₆-alkyl- group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen atom, C₁-C₃-alkyl-,C₃-C₆-cycloalkyl-, C₃-C₆-heterocyclyl-, phenyl, heteroaryl, wherein saidC₃-C₆-cycloalkyl-, C₃-C₆-heterocyclyl-, phenyl- or heteroaryl group isoptionally substituted with one substituent selected from halogen.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from halogen, halo-C₁-C₃-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from halogen, cyano, halo-C₁-C₃-alkyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl- group, which is substituted withone or two or three substituents, identically or differently, selectedfrom the group of a halogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl- group, which is substituted withone or two or three substituents, identically or differently, selectedfrom the group of a chloro or fluoro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₁-C₃-alkyl- group, which is substituted withone or two or three substituents selected from the group of a fluoroatom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a C₁-C₃-alkyl group.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a group selected from methyl, (²H₃)methyl.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a methyl group.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₅-C₆-cycloalkyl- group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₅-C₆-cycloalkyl- group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of fluoro, chloro, hydroxy,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a cyclopentyl or cyclohexyl group, which isoptionally substituted with one or two or three substituents,identically or differently, selected from the group of fluoro, chloro,hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₂-alkyl-,halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-, C₂-C₃-alkenyl-,C₂-C₃-alkynyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, whichC₃-C₆-cycloalkyl group is optionally substituted with one or two orthree substituents, identically or differently, selected from halogen,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a C₃-C₆-cycloalkyl-CH₂-group, whichC₃-C₆-cycloalkyl group is optionally substituted with one or two orthree substituents, identically or differently, selected from halogen,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a cyclohexyl-CH₂- or cyclopentyl-CH₂-group,which cyclohexyl or cyclopentyl group is optionally substituted with oneor two or three substituents, identically or differently, selected fromhalogen, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heterocyclyl-C₁-C₃-alkyl- group, whichheterocyclyl group is optionally substituted with one or two or threesubstituents, identically or differently, selected from halogen,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heterocyclyl-CH₂- group, which heterocyclylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from halogen, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a 4- to 7-membered heterocyclic ring, which isoptionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,—NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl group, which is optionally substitutedwith one or two or three substituents, identically or differently,selected from the group of halogen, hydroxy, —NH₂, alkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl group, which is optionally substitutedwith one or two or three substituents, identically or differently,selected from the group of halogen, hydroxy, —NH₂, alkylamino-,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-,C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₃-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,—NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; —C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₃-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₃-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen orC₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₃-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a phenyl-C₁-C₃-alkyl- group.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₂-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a phenyl-C₁-C₂-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a benzyl group, which phenyl group is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₃-alkyl- group , whichheteroaryl group is optionally substituted with one or two substituents,identically or differently, selected from the group of halogen, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₂-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,—NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two substituents,identically or differently, selected from the group of halogen, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a pyridyl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen orC₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a heteroaryl-C₁-C₂-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a pyridyl-C₁-C₂-alkyl- group, which pyridyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a pyridyl-CH₂-group, which pyridyl group isoptionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen,C₁-C₂-alkyl-, halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, C₁-C₂-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶, R⁷ represent, independently from each other, a groupselected from a hydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ and R⁷ represent, independently from each other, a groupselected from a hydrogen or fluoro atom or C₁-C₃-alkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶, R⁷ represent, independently from each other, a groupselected from a hydrogen atom, a fluoro atom or a chloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ and R⁷ represent, independently from each other, a groupselected from a hydrogen or fluoro atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents hydrogen, para-fluoro, orpara-chloro, whereby para refers to the point of attachment of R² to therest of the molecule, and in which R⁷ represents a hydrogen atom.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ represents para-fluoro, wherebypara refers to the point of attachment of R² to the rest of themolecule, and in which R⁷ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom, fluoroatom, chloro atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a fluoro atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents hydrogen, para-fluoro, orpara-chloro, whereby para refers to the point of attachment of R² to therest of the molecule.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁶ represents para-fluoro, wherebypara refers to the point of attachment of R² to the rest of themolecule.

In another embodiment the invention relates to compounds of formula (I),in which R⁷ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁷ represents a group selected from a hydrogen atom, fluoroatom, chloro atom, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, halo-C₁-C₂-alkyl-,C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁷ represents a group selected from a hydrogen atom, fluoroatom, chloro atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁷ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a fluoro atom and R⁷ represents a hydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁶ is in para position to the 5-fluoro pyrimidine andrepresents a fluoro atom and in which R⁷ represents a hydrogen atom.

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of formula (I), supra.

More particularly still, the present invention covers compounds offormula (I) which are disclosed in the Example section of this text,infra.

Very specially preferred are combinations of two or more of theabovementioned preferred embodiments.

In particular, preferred subjects of the present invention are thecompounds:

-   -   6-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine    -   6-(4-Fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine    -   6-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfonyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyrimidin-4-amine    -   6-(4-Fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine        or its salts, solvates or salts of solvates.

The abovementioned definitions of radicals which have been detailed ingeneral terms or in preferred ranges also apply to the end products ofthe formula (I) and, analogously, to the starting materials orintermediates required in each case for the preparation.

In another embodiment, the present invention concerns compounds ofgeneral formula (5)

wherein R¹, R², R³ and R⁴ are as defined for the compound of generalformula (I) according to the invention.

The invention furthermore relates to a method for the preparation of thecompounds of formula (I) according to the invention, in which method acompound of formula (5)

in which R¹, R², R³ and R⁴ are as defined for the compound of generalformula (I), is oxidized with an alkali salt of permanganic acid in analiphatic ketone of the formula C₁-C₂-alkyl-C(═O)—C₁-C₂-alkyl as asolvent, thus providing a compound of general formula (I) according tothe present invention, and in which method the resulting compound offormula (I) is optionally, if appropriate, reacted with thecorresponding (i) solvents and/or (ii) bases or acids to the solvates,salts and/or solvates of the salts of the compounds of formula (I).

The invention furthermore relates to a method for the preparation of thecompounds of formula (5), in which R¹, R², R³ and R⁴ are as defined forthe compound of general formula (I), in which method a compound offormula (3)

in which R² is as defined for the compound of general formula (I), isreacted with a pyridin-2-amine of formula (4)

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I), in the presence of tris(dibenzylideneacetone)dipalladium(0)and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), an alkalicarbonate as a base, and a cyclic ether as a solvent, to give a compoundof formula (5)

in which R¹, R², R³ and R⁴ are as defined for the compound of generalformula (I), by means of a Palladium-catalyzed C—N cross-couplingreaction.

The compounds according to the invention show a valuable pharmacologicaland pharmacokinetic spectrum of action which could not have beenpredicted.

They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of disorders in humans and animals.

Within the scope of the present invention, the term “treatment” includesprophylaxis.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their action as inhibitors of CDK9. Thus, thecompounds according to the general formula (I) as well aspharmaceutically acceptable salts thereof are used as inhibitors forCDK9.

Furthermore, the compounds according to the invention show aparticularly high potency (demonstrated by a low IC₅₀ value in theCDK9/CycT1 assay) for inhibiting CDK9 activity.

In context of the present invention, the IC₅₀ value with respect to CDK9can be determined by the methods described in the method section below.Preferably, it is determined according to Method 1a. (“CDK9/CycT1 kinaseassay”) described in the Materials and Method section below.

Surprisingly it turned out that the compounds according to the generalformula (I) as well as pharmaceutically acceptable salts thereofselectively inhibit CDK9 in comparison to other cyclin-dependent proteinkinases, preferably in comparison to CDK2. Thus, the compounds accordingto the general formula (I) as well as pharmaceutically acceptable saltsthereof are preferably used as selective inhibitors for CDK9.

Compounds of the present invention according to general formula (I) showa significantly stronger CDK9 than CDK2 inhibition.

In context of the present invention, the IC₅₀ value with respect to CDK2can be determined by the methods described in the method section below.Preferably, it is determined according to Method 2. (“CDK2/CycE kinaseassay”) described in the Materials and Method section below.

Further, as compared to the CDK9 inhibitors described in the prior art,preferred compounds of the present invention according to generalformula (I) show a surprisingly high potency for inhibiting CDK9activity at high ATP concentrations, which is demonstrated by their lowIC₅₀ value in the CDK9/CycT1 high ATP kinase assay. Thus, thesecompounds have a lower probability to be competed out of the ATP-bindingpocket of CDK9/CycT1 kinase due to the high intracellular ATPconcentration (R. Copeland et al., Nature Reviews Drug Discovery 2006,5, 730-739). According to this property the compounds of the presentinvention are particularly able to inhibit CDK9/CycT1 within cells for alonger period of time as compared to classical ATP competitive kinaseinhibitors. This increases the anti-tumor cell efficacy atpharmacokinetic clearance-mediated declining serum concentrations of theinhibitor after dosing of a patient or an animal.

In context of the present invention, the IC₅₀ value with respect to CDK9at high ATP concentrations can be determined by the methods described inthe method section below. Preferably, it is determined according toMethod 1b (“CDK9/CycT1 high ATP kinase assay”) as described in theMaterials and Method section below.

Further, preferred compounds of the present invention according toformula (I) show an improved anti-proliferative activity in tumor celllines such as HeLa compared to the CDK9 inhibitors described in theprior art. In context of the present invention, the anti-proliferativeactivity in tumor cell lines such as HeLa is preferably determinedaccording to Method 3. (“Proliferation Assay”) as described in theMaterials and Method section below.

Further, preferred compounds of the present invention according toformula (I) are characterized by improved pharmacokinetic properties,such as an increased apparent Caco-2 permeability (P_(app) A−B) acrossCaco-2 cell monolayers, compared to the compounds known from the priorart.

Further, preferred compounds of the present invention according toformula (I) are characterized by improved pharmacokinetic properties,such as a decreased efflux ratio (efflux ratio=P_(app) B−A/P_(app) A−B)from the basal to apical compartment across Caco-2 cell monolayers,compared to the compounds known from the prior art.

In context of the present invention, the apparent Caco-2 permeabilityvalues from the basal to apical compartment (P_(app) A−B) or the effluxratio (defined as the ratio ((P_(app) B−A)/(P_(app) A−B)) are preferablydetermined according to Method 4. (“Caco-2 Permeation Assay”) describedin the Materials and Method section below.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, preferably of disordersrelating to or mediated by CDK9 activity, in particular ofhyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases, more preferably ofhyper-proliferative disorders.

The compounds of the present invention may be used to inhibit theactivity or expression of CDK9. Therefore, the compounds of formula (I)are expected to be valuable as therapeutic agents. Accordingly, inanother embodiment, the present invention provides a method of treatingdisorders relating to or mediated by CDK9 activity in a patient in needof such treatment, comprising administering to the patient an effectiveamount of a compound of formula (I) as defined above. In certainembodiments, the disorders relating to CDK9 activity arehyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases, more preferably hyper-proliferativedisorders, particularly cancer.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable ofsuffering from a cell proliferative disorder or a disorder associatedwith reduced or insufficient programmed cell death (apoptosis) or whocould otherwise benefit from the administration of a compound of theinvention, such as human and non-human animals. Preferred humans includehuman patients suffering from or prone to suffering from a cellproliferative disorder or associated state, as described herein. Theterm “non-human animals” includes vertebrates, e.g., mammals, such asnon-human primates, sheep, cow, dog, cat and rodents, e.g., mice, andnon-mammals, such as chickens, amphibians, reptiles, etc.

The term “disorders relating to or mediated by CDK9” shall includediseases associated with or implicating CDK9 activity, for example thehyperactivity of CDK9, and conditions that accompany with thesediseases. Examples of “disorders relating to or mediated by CDK9”include disorders resulting from increased CDK9 activity due tomutations in genes regulating CDK9 activity such as LARP7, HEXIM1/2 or7sk snRNA, or disorders resulting from increased CDK9 activity due toactivation of the CDK9/cyclinT/RNApolymerase II complex by viralproteins such as HIV-TAT or HTLV-TAX or disorders resulting fromincreased CDK9 activity due to activation of mitogenic signalingpathways. The term “hyperactivity of CDK9” refers to increased enzymaticactivity of CDK9 as compared to normal non-diseased cells, or it refersto increased CDK9 activity leading to unwanted cell proliferation, or toreduced or insufficient programmed cell death (apoptosis), or mutationsleading to constitutive activation of CDK9.

The term “hyper-proliferative disorder” includes disorders involving theundesired or uncontrolled proliferation of a cell and it includesdisorders involving reduced or insufficient programmed cell death(apoptosis). The compounds of the present invention can be utilized toprevent, inhibit, block, reduce, decrease, control, etc., cellproliferation and/or cell division, and/or produce apoptosis. Thismethod comprises administering to a subject in need thereof, including amammal, including a human, an amount of a compound of this invention, ora pharmaceutically acceptable salt, hydrate or solvate thereof which iseffective to treat or prevent the disorder.

Hyper-proliferative disorders in the context of this invention include,but are not limited to, e.g., psoriasis, keloids and other hyperplasiasaffecting the skin, endometriosis, skeletal disorders, angiogenic orblood vessel proliferative disorders, pulmonary hypertension, fibroticdisorders, mesangial cell proliferative disorders, colonic polyps,polycystic kidney disease, benign prostate hyperplasia (BPH), and solidtumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid, and their distant metastases. Thosedisorders also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ, and canine or feline mammary carcinoma.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma, pleuropulmonary blastoma, and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers. Anal gland adenocarcinomas,mast cell tumors.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral, and hereditary andsporadic papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer, mast cell tumors.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer, and squamous cell cancer. Oral melanoma.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma. Malignant histiocytosis, fibrosarcoma,hemangiosarcoma, hemangiopericytoma, leiomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

Fibrotic proliferative disorders, i.e. the abnormal formation ofextracellular matrices, that may be treated with the compounds andmethods of the present invention include lung fibrosis, atherosclerosis,restenosis, hepatic cirrhosis, and mesangial cell proliferativedisorders, including renal diseases such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, transplant rejection, and glomerulopathies.

Other conditions in humans or other mammals that may be treated byadministering a compound of the present invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age-related maculardegeneration, rheumatoid arthritis, psoriasis, and bullous disordersassociated with subepidermal blister formation, including bullouspemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention may also be used to prevent andtreat diseases of the airways and the lung, diseases of thegastrointestinal tract as well as diseases of the bladder and bile duct.

The disorders mentioned above have been well characterized in humans,but also exist with a similar etiology in other animals, includingmammals, and can be treated by administering pharmaceutical compositionsof the present invention.

In a further aspect of the present invention, the compounds according tothe invention are used in a method for preventing and/or treatinginfectious diseases, in particular virally induced infectious diseases.The virally induced infectious diseases, including opportunisticdiseases, are caused by retroviruses, hepadnaviruses, herpesviruses,flaviviridae, and/or adenoviruses. In a further preferred embodiment ofthis method, the retroviruses are selected from lentiviruses oroncoretroviruses, wherein the lentivirus is selected from the groupcomprising: HIV-1, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV,preferably HIV-1 or HIV-2 and wherein the oncoretrovirus is selectedfrom the group of: HTLV-I, HTLV-II or BLV. In a further preferredembodiment of this method, the hepadnavirus is selected from HBV, GSHVor WHV, preferably HBV, the herpesivirus is selected from the groupcomprising: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV andthe flaviviridae is selected from HCV, West nile or Yellow Fever.

The compounds according to general formula (I) are also useful forprophylaxis and/or treatment of cardiovascular diseases such as cardiachypertrophy, adult congenital heart disease, aneurysm, stable angina,unstable angina, angina pectoris, angioneurotic edema, aortic valvestenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventriculardysplasia, arteriosclerosis, arteriovenous malformations, atrialfibrillation, Behcet syndrome, bradycardia, cardiac tamponade,cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cardiovascular disease prevention, carotidstenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes,Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterialendocarditis, fibromuscular dysplasia, congenital heart defects, heartdiseases, congestive heart failure, heart valve diseases, heart attack,epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia,hypertension, pulmonary hypertension, hypertrophic growth, leftventricular hypertrophy, right ventricular hypertrophy, hypoplastic leftheart syndrome, hypotension, intermittent claudication, ischemic heartdisease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome,long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneouslymph node syndrome, myocardial infarction, myocardial ischemia,myocarditis, pericarditis, peripheral vascular diseases, phlebitis,polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis,Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X,tachycardia, Takayasu's arteritis, hereditary hemorrhagictelangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot,thromboangiitis obliterans, thrombosis, thromboembolism, tricuspidatresia, varicose veins, vascular diseases, vasculitis, vasospasm,ventricular fibrillation, Williams syndrome, peripheral vasculardisease, varicose veins and leg ulcers, deep vein thrombosis,Wolff-Parkinson-White syndrome.

Preferred are cardiac hypertrophy, adult congenital heart disease,aneurysms, angina, angina pectoris, arrhythmias, cardiovascular diseaseprevention, cardiomyopathies, congestive heart failure, myocardialinfarction, pulmonary hypertension, hypertrophic growth, restenosis,stenosis, thrombosis and arteriosclerosis.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, in particular of thedisorders mentioned above.

A further subject matter of the present invention are the compoundsaccording to the invention for use in a method for the treatment and/orprophylaxis of the disorders mentioned above.

A preferred subject matter of the present invention are the compoundsaccording to the invention for the use in a method for the treatmentand/or prophylaxis of lung carcinomas, especially non-small cell lungcarcinomas, prostate carcinomas, especially hormone-independent humanprostate carcinomas, cervical carcinomas, including multidrug-resistanthuman cervical carcinomas, colorectal carcinomas, melanomas or ovariancarcinomas.

A further subject matter of the present invention is the use of thecompounds according to the invention in the manufacture of a medicamentfor the treatment and/or prophylaxis of disorders, in particular thedisorders mentioned above.

A preferred subject matter of the present invention is the use of thecompounds according to the invention in the manufacture of a medicamentfor the treatment and/or prophylaxis of lung carcinomas, especiallynon-small cell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas or ovarian carcinomas.

A further subject matter of the present invention is a method for thetreatment and/or prophylaxis of disorders, in particular the disordersmentioned above, using an effective amount of the compounds according tothe invention.

A preferred subject matter of the present invention is a method for thetreatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas or ovarian carcinomas.

Another aspect of the present invention relates to pharmaceuticalcombinations comprising a compound of general formula (I) according tothe invention in combination with at least one or more further activeingredients.

As used herein the term “pharmaceutical combination” refers to acombination of at least one compound of general formula (I) according tothe invention as active ingredient together with at least one otheractive ingredient with or without further ingredients, carrier, diluentsand/or solvents.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising a compound of general formula (I) according tothe invention in combination with an inert, nontoxic, pharmaceuticallysuitable adjuvant.

As used herein the term “pharmaceutical composition” refers to a galenicformulation of at least one pharmaceutically active agent together withat least one further ingredient, carrier, diluent and/or solvent.

Another aspect of the present invention relates to the use of thepharmaceutical combinations and/or the pharmaceutical compositionsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular of the disorders mentioned above.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thispharmaceutical combination includes administration of a singlepharmaceutical dosage formulation which contains a compound of formula(I) and one or more additional therapeutic agents, as well asadministration of the compound of formula (I) and each additionaltherapeutic agent in its own separate pharmaceutical dosage formulation.For example, a compound of formula (I) and a therapeutic agent may beadministered to the patient together in a single oral dosage compositionsuch as a tablet or capsule, or each agent may be administered inseparate dosage formulations.

Where separate dosage formulations are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate combination with other anti-tumor agents such asalkylating agents, anti-metabolites, plant-derived anti-tumor agents,hormonal therapy agents, topoisomerase inhibitors, camptothecinderivatives, kinase inhibitors, targeted drugs, antibodies, interferonsand/or biological response modifiers, anti-angiogenic compounds, andother anti-tumor drugs. In this regard, the following is a non-limitinglist of examples of secondary agents that may be used in combinationwith the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, bendamustin, and        mitolactol; platinum-coordinated alkylating compounds include,        but are not limited to, cisplatin, carboplatin, eptaplatin,        lobaplatin, nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as finasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-n1, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge; Merial melanoma vaccine    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofiran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, recentin, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, DAST, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, removab, revlimid,        sorafenib, vatalanib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab,        sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib        alaninate, vatalanib, pazopanib, and ranibizumab; Palladia    -   EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors        (such as e.g. RDEA 119) and Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifamib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib,        AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate,        brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;        Palladia, masitinib    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydro-chloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, amino-glutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemotherapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

Furthermore, the compounds of formula (I) may be utilized, as such or incompositions, in research and diagnostics, or as analytical referencestandards, and the like, which are well known in the art.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitable way,such as, for example, by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

For these administration routes, it is possible to administer thecompounds according to the invention in suitable application forms.

Suitable for oral administration are administration forms which work asdescribed in the prior art and deliver the compounds according to theinvention rapidly and/or in modified form, which comprise the compoundsaccording to the invention in crystalline and/or amorphous and/ordissolved form, such as, for example, tablets (coated or uncoated, forexample tablets provided with enteric coatings or coatings whosedissolution is delayed or which are insoluble and which control therelease of the compound according to the invention), tablets whichrapidly decompose in the oral cavity, or films/wafers,films/lyophilizates, capsules (for example hard or soft gelatincapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (for example intravenously, intraarterially, intracardially,intraspinally or intralumbally) or with inclusion of absorption (forexample intramuscularly, subcutaneously, intracutaneously,percutaneously or intraperitoneally). Administration forms suitable forparenteral administration are, inter alia, preparations for injectionand infusion in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (inter alia powder inhalers, nebulizers), nasaldrops/solutions/sprays; tablets to be administered lingually,sublingually or buccally, films/wafers or capsules, suppositories,preparations for the eyes or ears, vaginal capsules, aqueous suspensions(lotions, shaking mixtures), lipophilic suspensions, ointments, creams,transdermal therapeutic systems (such as plasters, for example), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, nontoxic, pharmaceutically suitable adjuvants.These adjuvants include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (for exampleliquid polyethylene glycols), emulsifiers and dispersants or wettingagents (for example sodium dodecyl sulphate, polyoxysorbitan oleate),binders (for example polyvinylpyrrolidone), synthetic and naturalpolymers (for example albumin), stabilizers (for example antioxidants,such as, for example, ascorbic acid), colorants (for example inorganicpigments, such as, for example, iron oxides) and flavour- and/orodour-masking agents.

The present invention furthermore provides medicaments comprising atleast one compound according to the invention, usually together with oneor more inert, nontoxic, pharmaceutically suitable adjuvants, and theiruse for the purposes mentioned above.

When the compounds of the present invention are administered aspharmaceuticals, to humans or animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably 0.5% to 90%) of active ingredient in combination with one ormore inert, nontoxic, pharmaceutically suitable adjuvants.

Regardless of the route of administration selected, the compounds of theinvention of general formula (I) and/or the pharmaceutical compositionof the present invention are formulated into pharmaceutically acceptabledosage forms by conventional methods known to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient without being toxic to the patient.

Materials and Methods:

The percentage data in the following tests and examples are percentagesby weight unless otherwise indicated; parts are parts by weight. Solventratios, dilution ratios and concentration data of liquid/liquidsolutions are in each case based on volume.

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

The in vitro pharmacological properties of the compounds can bedetermined according to the following assays and methods.

1a. CDK9/CycT1 Kinase Assay:

CDK9/CycT1—inhibitory activity of compounds of the present invention wasquantified employing the CDK9/CycT1 TR-FRET assay as described in thefollowing paragraphs:

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchased from Invitrogen (Cat. No PV4131). As substrate for the kinasereaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus inamid form) was used which can be purchased e.g. form the company JERINIPeptide Technologies (Berlin, Germany). For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipettedinto a black low volume 384 well microtiter plate (Greiner Bio-One,Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 in aqueousassay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl₂, 1.0 mM dithiothreitol,0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] wereadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc.in the 5 μl assay volume is 10 μM) and substrate (1.67 μM=>final conc.in the 5 μl assay volume is 1 μM) in assay buffer and the resultingmixture was incubated for a reaction time of 25 min at 22° C. Theconcentration of CDK9/CycT1 was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 1 μg/mL. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

1b. CDK9/CycT1 High ATP Kinase Assay

CDK9/CycT1-inhibitory activity of compounds of the present invention ata high ATP concentration after preincubation of enzyme and testcompounds was quantified employing the CDK9/CycT1 TR-FRET assay asdescribed in the following paragraphs.

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchase from Invitrogen (Cat. No PV4131). As substrate for the kinasereaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus inamid form) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany). For the assay 50 n1 of a 100fold concentrated solution of the test compound in DMSO was pipettedinto a black low volume 384 well microtiter plate (Greiner Bio-One,Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 in aqueousassay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl₂, 1.0 mM dithiothreitol,0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] wereadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of adenosine-tri-phosphate (ATP, 3.3 mM=>final conc.in the 5 μl assay volume is 2 mM) and substrate (1.67 μM=>final conc. inthe 5 μl assay volume is 1 μM) in assay buffer and the resulting mixturewas incubated for a reaction time of 25 mM at 22° C. The concentrationof CDK9/CycT1 was adjusted depending of the activity of the enzyme lotand was chosen appropriate to have the assay in the linear range,typical concentrations were in the range of 0.5 μg/mL. The reaction wasstopped by the addition of 5 μl of a solution of TR-FRET detectionreagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays, Codolet, France]and 1 nM anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389]and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer,product no. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.2%(w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

2a. CDK2/CycE Kinase Assay:

CDK2/CycE-inhibitory activity of compounds of the present invention wasquantified employing the CDK2/CycE TR-FRET assay as described in thefollowing paragraphs:

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchased fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIPeptide Technologies (Berlin, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10mM MgCl₂, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01%(v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for15 min at 22° C. to allow pre-binding of the test compounds to theenzyme before the start of the kinase reaction. Then the kinase reactionwas started by the addition of 3 μl of a solution ofadenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5 μl assayvolume is 10 μM) and substrate (1.25 μM=>final conc. in the 5 μl assayvolume is 0.75 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 25 min at 22° C. The concentration ofCDK2/CycE was adjusted depending of the activity of the enzyme lot andwas chosen appropriate to have the assay in the linear range, typicalconcentrations were in the range of 130 ng/mL. The reaction was stoppedby the addition of 5 μl of a solution of TR-FRET detection reagents (0.2μM streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nManti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100° A inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

2b. CDK2/CycE High ATP Kinase Assay

CDK2/CycE-inhibitory activity of compounds of the present invention at 2mM adenosine-tri-phosphate (ATP) was quantified employing the CDK2/CycETR-FRET (TR-FRET=Time Resolved Fluorescence Energy Transfer) assay asdescribed in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchase fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10mM MgCl₂, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01%(v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for15 min at 22° C. to allow pre-binding of the test compounds to theenzyme before the start of the kinase reaction. Then the kinase reactionwas started by the addition of 3 μl of a solution ATP (3.33 mM=>finalconc. in the 5 μl assay volume is 2 mM) and substrate (1.25 μM=>finalconc. in the 5 μl assay volume is 0.75 μM) in assay buffer and theresulting mixture was incubated for a reaction time of 25 mM at 22° C.The concentration of CDK2/CycE was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 15 ng/ml. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077, as an alternative aTerbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassayscan be used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v)bovine serum albumin in 100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm wer measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

3. Proliferation Assay:

Cultivated tumour cells (HeLa, human cervical tumour cells, ATCC CCL-2;NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177;A2780, human ovarian carcinoma cells, ECACC #93112519; DU 145,hormone-independent human prostate carcinoma cells, ATCC HTB-81;HeLa-MaTu-ADR, multidrug-resistant human cervical carcinoma cells,EPO-GmbH Berlin; Caco-2, human colorectal carcinoma cells, ATCC HTB-37;B16F10, mouse melanoma cells, ATCC CRL-6475) were plated at a density of5,000 cells/well (DU145, HeLa-MaTu-ADR), 3,000 cells/well (NCI-H460,HeLa), 2,500 cells/well (A2780), 1,500 cells/well (Caco-2), or 1,000cells/well (B16F10) in a 96-well multititer plate in 200 μL of theirrespective growth medium supplemented 10% fetal calf serum. After 24hours, the cells of one plate (zero-point plate) were stained withcrystal violet (see below), while the medium of the other plates wasreplaced by fresh culture medium (200 μl), to which the test substanceswere added in various concentrations (0 μM, as well as in the range of0.001-10 μM; the final concentration of the solvent dimethyl sulfoxidewas 0.5%). The cells were incubated for 4 days in the presence of testsubstances. Cell proliferation was determined by staining the cells withcrystal violet: the cells were fixed by adding 20 μl/measuring point ofan 11% glutaric aldehyde solution for 15 minutes at room temperature.After three washing cycles of the fixed cells with water, the plateswere dried at room temperature. The cells were stained by adding 100μl/measuring point of a 0.1% crystal violet solution (pH 3.0). Afterthree washing cycles of the stained cells with water, the plates weredried at room temperature. The dye was dissolved by adding 100μl/measuring point of a 10% acetic acid solution. The extinction wasdetermined by photometry at a wavelength of 595 nm. The change of cellnumber, in percent, was calculated by normalization of the measuredvalues to the extinction values of the zero-point plate (=0%) and theextinction of the untreated (0 μm) cells (=100%). The IC₅₀ values(inhibitory concentration at 50% of maximal effect) were determined bymeans of a 4 parameter fit.

Non-adherent MOLM-13 human acute myeloid leukemia cells (DSMZ ACC 554)were seeded at a density of 5,000 cells/well in a 96-well multititerplate in 100 μL of growth medium supplemented 10% fetal calf serum.After 24 hours, cell viability of one plate (zero-point plate) wasdetermined with the Cell Titre-Glo Luminescent Cell Viability Assay(Promega), while 50 μL of test compound containing medium was added tothe wells of the other plates (final concentrations in the range of0.001-10 μM and DMSO controls; the final concentration of the solventdimethyl sulfoxide was 0.5%). Cell viability was assessed after 72-hourexposure with the Cell Titre-Glo Luminescent Cell Viability Assay(Promega). IC₅₀ values (inhibitory concentration at 50% of maximaleffect) were determined by means of a 4 parameter fit on measurementdata which were normalized to vehicle (DMSO) treated cells (=100%) andmeasurement readings taken immediately before compound exposure (=0%).

4. Caco-2 Permeation Assay:

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cells per well on 24 well insert plates, 0.4 μmpore size, and grown for 15 days in DMEM medium supplemented with 10%fetal bovine serum, 1% GlutaMAX (100x, GIBCO), 100 U/mL penicillin, 100μg/mL streptomycin (GIBCO) and 1% non essential amino acids (100×).Cells were maintained at 37° C. in a humified 5% CO2 atmosphere. Mediumwas changed every 2-3 day. Before running the permeation assay, theculture medium was replaced by a FCS-free hepes-carbonate transportbuffer (pH 7.2). For assessment of monolayer integrity thetransepithelial electrical resistance (TEER) was measured. Testcompounds were predissolved in DMSO and added either to the apical orbasolateral compartment in final concentration of 2 μM in transportbuffer. Before and after 2h incubation at 37° C. samples were taken fromboth compartments. Analysis of compound content was done afterprecipitation with methanol by LC/MS/MS analysis. Permeability (Papp)was calculated in the apical to basolateral (A →B) and basolateral toapical (B→A) directions. The apparent permeability was calculated usingfollowing equation:Papp=(Vr/Po)(1/S)(P2/t)

Where Vr is the volume of medium in the receiver chamber, Po is themeasured peak area or height of the test drug in the donor chamber att=o, S the surface area of the monolayer, P2 is the measured peak areaof the test drug in the acceptor chamber after 2h of incubation, and tis the incubation time. The efflux ratio basolateral (B) to apical (A)was calculated by dividing the Papp B-A by the Papp A-B. In addition thecompound recovery was calculated. The following reference compounds wereused for the classification of the permeability class: Antipyrine,Pyrazosin, Verapamil, Fluvastatin, Cimetidine, Ranitidine, Atenolol,Sulfasalazine.

5. Carbonic Anhydrase Assay

The principle of the assay is based on the hydrolysis of 4-nitrophenylacetate by carbonic anhydrases (Pocker & Stone, Biochemistry, 1967, 6,668), with subsequent photometric determination of the dye product4-nitrophenolate at 400 nm by means of a 96-channel spectral photometer.

2 μL of the test compounds, dissolved in DMSO (100-fold finalconcentration), in a concentration range of 0.03-10 μmol/L (final), waspipetted as quadruplicates into the wells of a 96-hole microtiter plate.Wells that contained the solvent without test compounds were used asreference values (1. Wells without carbonic anhydrase for correction ofthe non-enzymatic hydrolysis of the substrate, and 2. Wells withcarbonic anhydrase for determining the activity of the non-inhibitedenzyme).

188 μL of assay buffer (10 mmol/L of Tris/HCl, pH 7.4, 80 mmol/L ofNaCl), with or without 3 units/well of carbonic anhydrase-1 [=humancarbonic anhydrase-1 (Sigma, #C4396)] in order to determine carbonicanhydrase-1 inhibition or 3 units/well of carbonic anhydrase-2 [=humancarbonic anhydrase-2 (Sigma, #C6165)] for measuring carbonic anhydrase-2inhibition, was pipetted into the wells of the microtiter plate. Theenzymatic reaction was started by the addition of 10 microL of thesubstrate solution (1 mmol/L of 4-nitrophenyl acetate (Fluka #4602),dissolved in anhydrous acetonitrile (final substrate concentration: 50μmol/L). The plate was incubated at room temperature for 15 minutes.Absorption was measured by photometry at a wavelength of 400 nm. Theenzyme inhibition was calculated after the measured values werenormalized to the absorption of the reactions in the wellswithout enzyme(=100% inhibition) and to the absorption of reactions in the wells withnon-inhibited enzyme (=0% inhibition). IC₅₀ values were determined bymeans of a 4 parameter fit using the company's own software.

PREPARATIVE EXAMPLES Syntheses of Compounds

The syntheses of the N-(pyridin-2-yl)pyrimidin-4-amine derivativesaccording to the present invention are preferably carried out accordingto the general synthetic sequence, shown in scheme 1.

In the first step, 4,6-dichloropyrimidine (CAS No.: 1193-21-1; 1) isreacted with a boronic acid derivative R²—B(OR)₂ of formula (2), whereinR² is as defined for the compound of general formula (I), to give acompound of formula (3). The boronic acid derivative (2) may be aboronic acid (R=—H) or an ester of the boronic acid, e.g. its isopropylester (R=—CH(CH₃)₂), preferably an ester derived from pinacol in whichthe boronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R=—C(CH₃)₂—C(CH₃)₂—).

The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0)catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts like dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction is preferably carried out in a mixture of a solvent like1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with waterand in the presence of a base like potassium carbonate, sodiumbicarbonate or potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction is performed at temperatures ranging from room temperature(i.e. approx. 20° C.) to the boiling point of the respective solvent.Further on, the reaction can be performed at temperatures above theboiling point using pressure tubes and a microwave oven. The reaction ispreferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (3), in which R² is as definedfor the compound of general formula (I), is reacted with apyridin-2-amine of formula (4), in which R¹, R³ and R⁴ are as definedfor the compound of general formula (I), to give a compound of formula(5). This coupling reaction can be carried out by a Palladium-catalyzedC—N cross-coupling reactions (for a review on C—N cross couplingreactions see for example: a) L. Jiang, S. L. Buchwald in‘Metal-Catalyzed Cross-Coupling Reactions’, 2nd ed.: A. de Meijere, F.Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use oftris(dibenzylideneacetone)dipalladium(0) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane). An alkalicarbonate, preferably cesium carbonate is used as a base, and a cyclicether, preferably dioxane, is used as a solvent. The reactions arepreferably run under argon for 3-48 hours at 100° C. in a microwave ovenor in an oil bath. Pyridine-2-amines of formula (4) are commerciallyavailable in certain cases, or can be prepared by methods known to theperson skilled in the art, e.g. from the corresponding4-hydroxymethylpyridine-2-amine via conversion of the hydroxy groupcontained therein into a suitable leaving group, such as chloro orbromo, followed by nucleophilic displacement with a thiol of the generalformula (9). If needed, the amino group present in said4-hydroxymethylpyridine-2-amine can be protected by a suitableprotecting group. Protecting groups for amino groups present inanalogues and methods for their introduction and removal are well knownto the person skilled in the art, see e.g. T. W. Greene and P. G. M.Wuts in: Protective Groups in Organic Synthesis, 3^(rd) edition, Wiley(1999).

In the third step, a compound of formula (5), in which R¹, R², R³and R⁴are as defined for the compound of general formula (I), is oxidized tothe corresponding sulfone of formula (I) with an alkali salt ofpermanganic acid in an aliphatic ketone of the formulaC₁-C₂-alkyl-C(═O)—C₁-C₂-alkyl as a solvent. Preferred is the hereindescribed use of potassium permanganate in acetone. The reactions arepreferably run at 40-70° C.

An alternative synthesis approach to theN-(pyridin-2-yl)pyrimidin-4-amine derivatives according to the presentinvention is described in scheme 2.

In the first step, a compound of formula (3), in which R² is as definedfor the compound of general formula (I), is reacted with a suitablepyridin-2-amine of formula (6), in which R³ and R⁴ are as defined forthe compound of general formula (I), to give a compound of formula (7).This coupling reaction can be carried out by a Palladium-catalyzed C—Ncross-coupling reactions (for a review on C—N cross coupling reactionssee for example: a) L. Jiang, S. L. Buchwald in ‘Metal-CatalyzedCross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere, F. Diederich,Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred is the hereindescribed use of tris(dibenzylideneacetone)dipalladium(0),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and cesiumcarbonate in dioxane. The reactions are preferably run under argon for3-48 hours at 100° C. in a microwave oven or in an oil bath.

Pyridine-2-amines of formula (6) are commercially available in certaincases, or can be prepared by methods known to the person skilled in theart, e.g. by reduction of the corresponding carboxylic acids or estersthereof.

In the second step, a compound of formula (7), in which R², R³ and R⁴are as defined for the compound of general formula (I), is converted toa compound of formula (8), in which R², R³ and R⁴ are as defined for thecompound of general formula (I) and in which LG represents a leavinggroup, preferably chloro or bromo. Preferred is the herein described useof thionyl chloride in NMP or DMF and DCM for the formation therespective chloromethyl pyridines (LG=C1). A possibility for theformation of the respective bromomethyl pyridines (LG=Br) is the use oftetrabromomethane and triphenylphosphane in DCM (see for example: Pollaet al, Bioorganic and Medicinal Chemistry, 2004, 12, 1151).

In the third step, a compound of formula (8) is converted to a thioetherof formula (5), in which R¹, R², R³ and R⁴ are as defined for thecompound of general formula (I), by reaction with suitable thiols offormula (9), in which R¹ is as defined for the compound of formula (I),under basic conditions, yielding the corresponding thioethers of formula(5) (see for example: Sammond et al, Bioorg. Med. Chem. Lett. 2005, 15,3519). Thiols of formula (9) are known to the person skilled in the artand are commercially available in considerable variety.

In the final step, the thioether of formula (5) is oxidized to thecorresponding sulfone of formula (I) as described in scheme 1.

Another alternative synthesis approach to theN-(pyridin-2-yl)pyrimidin-4-amine derivatives of formula (I) accordingto the present invention is described in scheme 3.

In the first step, 6-chloropyrimidin-4-amine (CAS No.: 5305-59-9; 10) isreacted with a boronic acid derivative R²—B(OR)₂ of formula (2), whereinR² is as defined for the compound of general formula (I), to give acompound of formula (11). The boronic acid derivative (2) may be aboronic acid (R=—H) or an ester of the boronic acid, e.g. its isopropylester (R=—CH(CH₃)₂), preferably an ester derived from pinacol in whichthe boronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R=—C(CH₃)₂—C(CH₃)₂—).

The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0)catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts like dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction is preferably carried out in a mixture of a solvent like1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with waterand in the presence of a base like potassium carbonate, sodiumbicarbonate or potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction is performed at temperatures ranging from room temperature(i.e. approx. 20° C.) to the boiling point of the respective solvent.Further on, the reaction can be performed at temperatures above theboiling point using pressure tubes and a microwave oven. The reaction ispreferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (11) is reacted with asuitable pyridine derivative of formula (12), in which R¹, R³ and R⁴ areas defined for the compound of general formula (I), and in which LGrepresents a leaving group, preferably chloro, to give a compound offormula (5). This coupling reaction can be carried out by aPalladium-catalyzed C—N cross-coupling reaction (for a review on C—Ncross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere,F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred isthe herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl and potassiumphosphate in toluene and NMP. The reactions are preferably run underargon for 2-24 hours at 100-130° C. in a microwave oven or in an oilbath.

In the final step, the thioether of formula (5) is converted to thecorresponding sulfone of formula (I) by oxidation as described in scheme1.

Pyridine derivatives of the formula (12) can be prepared according tomethods known to the person skilled in the art, e.g. by conversion of ahalomethyl group into the thioether present in compound of the formula(12) using a thiol of the formula (9), in which R¹ is as defined for thecompound of general formula (I), in a similar fashion as described suprafor pyridine amines of the formula (4) and for the conversion ofintermediates of formula (8) into thioethers of formula (5) in scheme 2.Said halomethyl pyridine precursors are known to the person skilled inthe art, can be prepared e.g. from the corresponding hydroxymethylpyridines in analogy to the conversion of compounds of formula (7) intocompounds of formula (8) described supra, and are commercially availablein certain cases.

A further alternative approach to the compounds of general formula (I)is shown in Scheme 4. In a first step, sulfones of formula (15) can besynthesised starting from aminopyridine derivatives of the formula (13),in which R³ and R⁴ are as defined for the compound of general formula(I), and in which LG represents a leaving group as defined herein,preferably chloro or bromo, which are reacted with sulfinate salts ofthe formula (14), in which R¹ is as defined for the compound of generalformula (I) and in which stands for a cation of an alkali metal, such assodium, potassium or cesium (see e.g. a) Lewis et al, Tetrahedron 2011,67, 7517; b) Lucking et al, WO 2012/143399; c) Lucking et al, WO2013/37896), to give sulfones of the formula (15).

In a second step, compounds of the formula (3), in which R² is asdefined for the compound of general formula (I), are subjected to acoupling reaction with said sulfones of formula (15), in which R¹, R³and R⁴ are as defined for the compound of general formula (I). Thiscoupling reaction can be carried out by a Palladium-catalyzed C—Ncross-coupling reaction (for a review on C—N cross coupling reactionssee for example: a) L. Jiang, S. L. Buchwald in ‘Metal-CatalyzedCross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere, F. Diederich,Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl and potassiumphosphate in toluene and NMP. The reactions are preferably run underargon for 2-24 hours at 100-130° C. in a microwave oven or in an oilbath.

Aminopyridine derivatives of formula (13) are known to the personskilled in the art and are commercially available in certain cases. Forthe synthesis of compounds of the formula (3), see Scheme 1.

Preparation of Compounds:

Abbreviations Used in the Description of the Chemistry and in theExamples that Follow are:

br (broad); CDCl₃ (deuterated chloroform); cHex (cyclohexane); d(doublet); DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DME(1,2-dimethoxyethane), DMF (dimethylformamide); DMSO (dimethylsulfoxide); eq (equivalent); ES (electrospray); EtOAc (ethyl acetate);EtOH (ethanol); iPrOH (iso-propanol); mCPBA (meta-chloroperoxybenzoicacid), MeCN (acetonitrile), MeOH (methanol); MS (mass spectrometry); NBS(N-bromosuccinimide), NMR (nuclear magnetic resonance); p (pentet);Pd(dppf)Cl₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane); iPrOH (iso-propanol); q(quartet); RT (room temperature); s (singlet); sat. aq. (saturatedaqueous); SiO₂ (silica gel); TFA (trifluoroacetic acid); TFAA(trifluoroacetic anhydride), THF (tetrahydrofuran); tr (triplet).

The IUPAC names of the examples were generated using the program‘ACD/Name batch version 12.01’ from ACD LABS.

EXAMPLE 16-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine

Preparation of Intermediate 1.1:4-Chloro-6-(4-fluoro-2-methoxyphenyl)pyrimidine

Under argon, a mixture of 4,6-dichloropyrimidine (5.00 g; 33.56 mmol),(4-fluoro-2-methoxyphenyl)boronic acid (6.27 g; 36.92 mmol; AldrichChemical Company Inc.) and[1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II) (2.74 g;3.36 mmol; Aldrich Chemical Company Inc.) in a 2M solution of potassiumcarbonate (50 mL) and 1,2-dimethoxyethane (101 mL) was stirred for 150minutes at 90° C. After cooling, the batch was diluted with ethylacetate and washed with diluted aqueous sodium chloride solution. Theorganic phase was filtered using a Whatman filter and concentrated. Theresidue was purified by chromatography (hexane/ethyl acetate 5% tohexane/ethyl acetate 40%) to give the desired product (6.35 g; 26.61mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=9.00 (m, 1H), 8.13 (m, 1H), 8.02 (m,1H), 6.82 (m, 1H), 6.75 (m, 1H), 3.94 (s, 3H).

Preparation of Intermediate 1.26-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]pyridin-2-yl}pyrimidin-4-amine

A batch with 4-chloro-6-(4-fluoro-2-methoxyphenyl)pyrimidine (201 mg;0.84 mmol), 4-[(methylsulfanyl)methyl]pyridin-2-amine (622 mg; 4.03mmol; UkrOrgSynthesis Ltd.),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (11 mg; 0.02mmol) and cesium carbonate (411 mg; 1.26 mmol) in dioxane (3.0 mL) wasdegassed using argon. Tris(dibenzylideneacetone)dipalladium(0) (6 mg;0.006 mmol) was added under argon and the batch was stirred for 5 hoursat 100° C. After cooling, the batch was diluted with an aqueous solutionof sodium chloride and extracted with ethyl acetate. The combinedorganic phases were filtered using a Whatman filter and concentrated.The residue was purified by chromatography (DCM/EtOH 9:1) to give thedesired product (190 mg; 0.53 mmol).

¹H NMR (400MHz, CDCl₃, 300K) δ=8.86 (m, 1H), 8.26 (m, 1H), 8.02 (m, 2H),7.94 (m, 1H), 7.83 (s, 1H), 6.96 (m, 1H), 6.77 (m, 2H), 3.91 (s, 3H),3.67 (s, 2H), 2.05 (s, 3H).

Preparation of End Product

Potassium permanganate (67 mg; 0.43 mmol) was added to a stirredsolution of6-(4-fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]pyridin-2-yl}pyrimidin-4-amine(61 mg; 0.17 mmol) in acetone (2.0 mL) at RT. The mixture was stirred at40° C. for one hour. After cooling, the batch was concentrated and theresidue was purified by chromatography (DCM/EtOH 95:5) to give thedesired product (14 mg; 0.04 mmol).

¹H NMR (400 MHz, d₆-DMSO, 300K) δ=10.33 (s, 1H), 8.78 (m, 1H), 8.33 (m,2H), 8.05 (m, 1H), 7.91 (s, 1H), 7.09 (m, 1H), 7.05 (m, 1H), 6.92 (m,1H), 4.57 (s, 2H), 3.93 (s, 3H), 3.02 (s, 3H).

Alternative Procedure for the Preparation of Intermediate 1.26-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]pyridin-2-yl}pyrimidin-4-amine

Preparation of Intermediate 1.3(2-{[6-(4-Fluoro-2-methoxyphenyl)pyrimidin-4-yl]amino}pyridin-4-yl)methanol

A batch with 4-chloro-6-(4-fluoro-2-methoxyphenyl)pyrimidine (383 mg;1.61 mmol), (2-aminopyridin-4-yl)methanol (199 mg; 1.61 mmol; ABCR GmbH& CO. KG), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)(418 mg; 0.72 mmol) and cesium carbonate (785 mg; 2.41 mmol) in dioxane(8.0 mL) was degassed using argon.Tris(dibenzylideneacetone)dipalladium(0) (147 mg; 0.16 mmol) was addedunder argon and the batch was stirred for 5 hours at 100° C. Aftercooling, the batch was diluted with ethyl acetate and washed with anaqueous solution of sodium chloride. The organic phase was filteredusing a Whatman filter and concentrated. The residue was purified bychromatography (DCM/EtOH 93:7) to give the desired product (97 mg; 0.30mmol).

¹H NMR (400 MHz, d₆-DMSO, 300K) δ=10.14 (s, 1H), 8.71 (m, 1H), 8.34 (s,1H), 8.20 (m, 1H), 8.00 (m, 1H), 7.77 (s, 1H), 7.06 (m, 1H), 6.88 (m,2H), 5.36 (tr, 1H), 4.49 (d, 2H), 3.89 (s, 3H).

Preparation of End Product (Alternative Preparation of Intermediate 1.2)

Thionylchloride (80 mg; 0.66 mmol) was added dropwise to a stirredsolution of(2-{[6-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl]amino}pyridin-4-yl)methanol(87 mg; 0.27 mmol) in DCM (1.5 ml) and NMP (0.2 ml) at 0° C. The mixturewas stirred for 17 hours at RT. The batch was diluted with ethylacetate, weakly basified with aqueous sodium bicarbonate solution andwashed with aqueous sodium chloride solution. The aqueous phases wereextracted with DCM (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to give crudeN-[4-(chloromethyl)pyridin-2-yl]-6-(4-fluoro-2-methoxyphenyl)pyrimidin-4-amine,that was used without further purification in the next step.

The residue was taken up in EtOH (2.0 ml) and the resulting solution wascooled to 0° C. Sodium methanethiolate (22 mg; 0.32 mmol) was added tothe stirred solution at 0° C. The mixture was stirred for 28 hours at RTbefore it was diluted with ethyl acetate and washed with aqueous sodiumchloride solution. The organic phase was filtered using a Whatman filterand concentrated. The residue was purified by chromatography(Hexane/ethyl acetate 3:2) to give the desired product (49 mg; 0.14mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.86 (m, 1H), 8.26 (m, 1H), 8.02 (m,2H), 7.94 (m, 1H), 7.83 (s, 1H), 6.96 (m, 1H), 6.77 (m, 2H), 3.91 (s,3H), 3.67 (s, 2H), 2.05 (s, 3H).

EXAMPLE 26-(4-Fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine

Preparation of Intermediate 2.1 (2-Chloro-6-methylpyridin-4-yl)methanol

To a stirred solution of 2-chloro-6-methylpyridine-4-carboxylic acid(10.00 g; 55.4 mmol; Maybridge,) in THF (100 mL) at 0° C. was added a 1Msolution of borane-tetrahydrofuran complex in THF (221.5 mL; 221.5mmol). The mixture was allowed to react at RT overnight. Then, MeOH (22mL) was cautiously added to the stirred mixture while cooling with anice bath. The batch was diluted with ethyl acetate and washed withaqueous sodium hydroxide solution (1N) and saturated aqueous sodiumchloride solution. The organic layer was filtered using a Whatman filterand concentrated. The residue was purified by column chromatography onsilica gel (DCM/EtOH 95:5) to give the pure product (7.24 g; 45.9 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=7.18 (s, 1H), 7.09 (s, 1H), 4.72 (d,2H), 2.55 (s, 3H), 2.17 (tr, 1H).

Preparation of Intermediate 2.22-Chloro-6-methyl-4-[(methylsulfanyl)methyl]pyridine

To a stirring solution of (2-chloro-6-methylpyridin-4-yl)methanol (7.20g; 45.7 mmol) in DMF (200 mL) at 0° C. was added dropwise thionylchloride (8.3 mL; 114.2 mmol). The mixture was allowed to react at 10°C. for 2 hours. Then, the mixture was concentrated to give the crudeproduct 2-chloro-4-(chloromethyl)-6-methylpyridine (17.08 g).

Crude 2-chloro-4-(chloromethyl)-6-methylpyridine (8.04 g) was dissolvedin acetone (250 mL) and an aqueous solution of sodium methanethiolate(21%, 18.3 mL, 54.8 mmol; Aldrich Chemical Company Inc.) was addeddropwise under stirring. The mixture was stirred at RT for 3 hoursbefore additional aqueous solution of sodium methanethiolate (21%, 15.3mL, 45.7 mmol; Aldrich Chemical Company Inc.) was added and the mixturewas stirred at RT overnight. Finally, additional aqueous solution ofsodium methanethiolate (21%, 15.3 mL, 45.7 mmol; Aldrich ChemicalCompany Inc.) was added and the mixture was stirred at RT for 6 hours.The batch was diluted with ethyl acetate and an aqueous solution ofsodium chloride. The mixture was extracted with ethyl acetate (2×). Thecombined organic layers were filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane to hexane/ethyl acetate 20%) to give the desiredproduct (7.05 g; 37.6 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=7.12 (s, 1H), 7.05 (s, 1H), 3.58 (s,2H), 2.54 (s, 3H), 2.03 (s, 3H).

Preparation of Intermediate 2.36-(4-Fluoro-2-methoxyphenyl)pyrimidin-4-amine

Under an atmosphere of argon, a mixture of 6-chloropyrimidin-4-amine(500 mg; 3.86 mmol; ABCR GmbH & CO. KG),(4-fluoro-2-methoxyphenyl)boronic acid (722 mg; 4.25 mmol; AldrichChemical Company Inc.) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (315 mg;0.39 mmol; Aldrich Chemical Company Inc.) in a 2M solution of potassiumcarbonate (5.8 mL) and 1,2-dimethoxyethane (11.6 mL) was stirred for 150minutes at 90° C. After cooling, the batch was diluted with ethylacetate and THF and washed with diluted aqueous sodium chloridesolution. The organic layer was filtered using a Whatman filter andconcentrated. The residue was purified by column chromatography onsilica gel (hexane to ethyl acetate) to give the desired product (636mg; 2.90 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.35 (m, 1H), 7.89 (m, 1H), 7.01 (m,1H), 6.96 (m, 1H) 6.83 (m, 1H), 6.78 (br, 2H), 3.84 (s, 3H).

Preparation of Intermediate 2.45-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine

A mixture of 6-(4-fluoro-2-methoxyphenyl)pyrimidin-4-amine (1752 mg;7.99 mmol), 2-chloro-6-methyl-4-[(methylsulfanyl)methyl]pyridine (1000mg; 5.33 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (441 mg; 0.53 mmol; ABCR GmbH & CO. KG)and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (254 mg;0.53 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (5655mg; 17.77 mmol) in toluene (111 ml) and NMP (15 mL) was stirred under anatmosphere of argon at 130° C. in a closed vessel for 4 hours. Aftercooling, the batch was diluted with ethyl acetate and washed withaqueous sodium chloride solution. The organic phase was filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 50%) togive the pure product (1600 mg; 4.32 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.87 (s, 1H), 8.07 (m, 1H), 7.99 (s,1H), 7.74 (br, 1H), 7.64 (s, 1H), 6.79 (m, 3H), 3.94 (s, 3H), 3.65 (s,2H), 2.51 (s, 3H), 2.08 (s, 3H).

Preparation of End Product

Potassium permanganate (107 mg; 0.68 mmol) was added to a stirredsolution of5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfanyl)methyl]pyridin-2-yl}pyridin-2-amine(100 mg; 0.27 mmol) in acetone (4.3 mL) at RT. The mixture was stirredat 40° C. for 3.5 hours. Additional potassium permanganate (43 mg; 0.27mmol) was added and the mixture was stirred for 1.5 hours at 40° C.After cooling, the batch was diluted with DCM and an aqueous solution ofsodium disulfite. The organic layer was separated and the aqueous layerwas extracted with DCM (2×). The combined organic layers were filteredusing a Whatman filter and concentrated. The residue was purified bypreparative HPLC to give the desired product (31 mg; 0.08 mmol).

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max.250 mg/max. 2.5 mL DMSO or DMF Injektion: 1 × 2.5 mL Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.87 (s, 1H), 8.09 (m, 1H), 7.96 (s,1H), 7.85 (br, 1H), 7.64 (br, 1H), 6.96 (s, 1H), 6.83 (m, 1H), 6.77 (m,1H), 4.27 (s, 2H), 3.95 (s, 3H), 2.93 (s, 3H), 2.54 (s, 3H).

EXAMPLE 36-(4-Fluoro-2-methoxyphenyl)-N-{1-[(methylsulfonyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyrimidin-4-amine

Preparation of Intermediate 3.12-Chloro-4-[(methylsulfanyl)methyl]-6-(trifluoromethyl)pyridine

To a stirred solution of4-(Bromomethyl)-2-chloro-6-(trifluoromethyl)pyridine (1000 mg; 3.64mmol; FCH Group Company) in acetone (40 mL) was added dropwise anaqueous solution of sodium methanethiolate (21%, 1.2 mL, 3.64 mmol;Aldrich Chemical Company Inc.). The mixture was stirred at RT for 7hours before the batch was diluted with ethyl acetate and an aqueoussolution of sodium chloride. The mixture was extracted with ethylacetate (2×). The combined organic layers were filtered using a Whatmanfilter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 20%) togive the desired product (716 mg; 2.96 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=7.61 (s, 1H), 7.50 (s, 1H), 3.70 (s,2H), 2.06 (s, 3H).

Preparation of Intermediate 3.26-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyrimidin-4-amine

A mixture of 6-(4-fluoro-2-methoxyphenyl)pyrimidin-4-amine (475 mg; 2.17mmol), 2-chloro-4-[(methylsulfanyl)methyl]-6-(trifluoromethyl)pyridine(349 mg; 1.44 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (119 mg; 0.14 mmol; ABCR GmbH & CO. KG)and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (69 mg; 0.14mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1533 mg;7.22 mmol) in toluene (30 ml) and NMP (4 mL) was stirred under anatmosphere of argon at 130° C. in a closed vessel for 4 hours. Aftercooling, the batch was diluted with DCM and washed with aqueous sodiumchloride solution. The organic layer was filtered using a Whatman filterand concentrated. The residue was purified by column chromatography onsilica gel (DCM to DCM/EtOH 5%) to give the pure product (550 mg; 1.30mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.91 (s, 1H), 8.15 (s, 1H), 8.09 (m,1H), 7.94 (s, 1H), 7.74 (br, 1H), 7.35 (m, 1H), 6.81 (m, 2H), 3.95 (s,3H), 3.74 (s, 2H), 2.09 (s, 3H).

Preparation of End Product

Example 3 was prepared under similar conditions as described in thepreparation of Example 2 using6-(4-fluoro-2-methoxyphenyl)-N-{4-[(methylsulfanyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyrimidin-4-amineand potassium permanganate. The product was purified by preparativeHPLC.

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max.250 mg/max. 2.5 mL DMSO or DMF Injektion: 1 × 2.5 mL Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z

¹H NMR (400 MHz, d₆-DMSO, 300K) δ=10.77 (s, 1H), 8.82 (m, 1H), 8.34 (m,1H), 8.22 (s, 1H), 8.03 (m, 1H), 7.49 (m, 1H), 7.10 (m, 1H), 6.92 (m,1H), 4.73 (s, 2H), 3.89 (s, 3H), 3.05 (s, 3H).

EXAMPLE 46-(4-Fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine

Preparation of Intermediate 4.1 (2,6-Difluoropyridin-4-yl)methanol

To a stirred solution of 2,6-difluoropyridine-4-carboxylic acid (5.32 g;32.8 mmol; Matrix Scientific, CAS #88912-23-6) in THF (85 mL) was addeda 1M solution of borane-tetrahydrofuran complex in THF (13.2 mL; 131.2mmol) at 0° C. The mixture was allowed to react at RT overnight. Then,MeOH (15.9 mL) was cautiously added to the stirred mixture while coolingwith an ice bath. The batch was diluted with ethyl acetate and washedwith aqueous sodium hydroxide solution (1N) and saturated aqueous sodiumchloride solution. The organic layer was filtered using a Whatman filterand concentrated to yield the title compound (4.85 g), which was usedwithout further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.06 (s, 2H), 5.68 (tr, 1H), 4.62 (d,2H).

Preparation of Intermediate 4.2 (2-Amino-6-fluoropyridin-4-yl)methanol

A mixture of (2,6-difluoropyridin-4-yl)methanol (330 mg; 2.27 mmol,intermediate 3.1) and 33% w/w aqueous solution of ammonia (19.8 ml) wasplaced into a microwave tube. The mixture was allowed to react at 110°C. for 6 hours in the sealed tube under microwave irradiation. Then, themixture was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with saturated aqueous sodiumchloride solution and dried over sodium sulfate. After evaporation theresidue was purified by column chromatography on silica gel(dichloromethane/methanol) to yield the title compound (209 mg, 1.41mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.28 (dd, 1H), 6.22 (s, 2H), 5.99 (s,1H), 5.28 (tr, 1H), 4.37 (d, 2H).

Preparation of Intermediate 4.3 4-(Chloromethyl)-6-fluoropyridin-2-amine

To a stirred solution of (2-amino-6-fluoropyridin-4-yl)methanol (194 mg;1.36 mmol, intermediate 3.2) in DCM (6.6 ml) and NMP (0.44 ml) at 0° C.was added dropwise thionyl chloride (0.25 mL; 3.41 mmol). The mixturewas allowed to react at room temperature overnight. The batch wasdiluted with aqueous sodium bicarbonate solution and aqueous sodiumchloride solution and extracted with DCM (3×). The combined organiclayers were filtered, dried over sodium sulfate, and concentrated. Thecrude material was purified by column chromatography on silica gel(dichloromethane/methanol) to yield the desired product (161 mg; 0.94mmol).

¹H-NMR (400 MHz, DMSO-d₆): 6 [ppm]=6.45 (s, 1H), 6.34 (d, 1H), 6.13 (s,1H), 4.61 (s, 2H).

Preparation of Intermediate 4.46-Fuoro-4-[(methylsulfonyl)methyl]pyridin-2-amine

A mixture of 4-(chloromethyl)-6-fluoropyridin-2-amine (50 mg; 0.31 mmoL)and sodium methanesulfinate (167 mg; 1.56 mmol; ABCR GmbH & CO. KG) inDMF (2.5 mL) was heated in a microwave oven at 60° C. for 8 hours. Aftercooling, the batch was concentrated and the residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate 12% to ethylacetate) to give the desired product (30 mg; 0.13 mmol).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.48 (s, 2H), 6.32 (m, 1H), 6.12 (s,1H), 4.39 (s, 2H), 2.94 (s, 3H).

Preparation of End Product

A mixture of 6-fluoro-4-[(methylsulfonyl)methyl]pyridin-2-amine (42 mg;0.199 mmol), 4-chloro-6-(4-fluoro-2-methoxyphenyl)pyrimidine (40 mg;0.159 mmol; intermediate 1.1),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (13 mg; 0.016 mmol; ABCR GmbH & CO. KG)and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (8 mg; 0.016mmol; Aldrich Chemical Company Inc.) and potassium phosphate (169 mg;0.796 mmol) in toluene (3.6 ml) and NMP (0.28 mL) was stirred under anatmosphere of argon at 130° C. in a closed vessel for 3 hours in amicrowave oven. After cooling, the batch was diluted with water andextracted with ethyl acetate (3×). The combined organic phases weredried (Na₂SO₄), filtered and concentrated. The residue was purified bypreparative HPLC to give the desired product (14 mg; 0.03 mmol).

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD 3001 Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min1-99% B, 8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max.250 mg/max. 2.5 mL DMSO or DMF Injektion: 1 × 2.5 mL Detection: DAD scanrange 210-400 nm MS ESI+, ESI−, scan range 160-1000 m/z

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.58 (s, 1H), 8.80 (m, 1H), 8.34 (s,1H), 8.10 (m, 1H), 7.84 (s, 1H), 7.10 (m, 1H), 6.92 (m, 1H), 6.75 (s,1H), 4.63 (s, 2H), 3.94 (s, 3H), 3.03 (s, 3H).

The following Table 1 provides an overview on the compounds described inthe example section:

TABLE 1 Example No. Structure Name of compound 1

6-(4-Fluoro-2-methoxyphenyl)-N-{4- [(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine 2

6-(4-Fluoro-2-methoxyphenyl)-N-{6- methyl-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine 3

6-(4-Fluoro-2-methoxyphenyl)-N-{4- [(methylsulfonyl)methyl]-6-(trifluoromethyl)pyridin-2-yl} pyrimidin-4-amine 4

6-(4-Fluoro-2-methoxyphenyl)-N-{6- fluoro-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amineResults:

TABLE 2 Inhibition for CDK9 and CDK2 of compounds according to thepresent invention {circle around (1)} Structure {circle around (2)}{circle around (3)} {circle around (4)} {circle around (5)} 1

3 280 16 20000 2

n.t. 90 2 2250 3

4 73 2 371 4

3 92 11 1870 The IC₅₀ (inhibitory concentration at 50% of maximaleffect) values are indicated in nM, “n.t.” means that the compounds havenot been tested in this assay. {circle around (1)} Example Number{circle around (2)} CDK9: CDK9/CycT1 kinase assay as described underMethod 1a. of Materials and Methods {circle around (3)} CDK2: CKD2/CycEkinase assay as described under Method 2a. of Materials and Methods{circle around (4)} high ATP CDK9: CDK9/CycT1 kinase assay as describedunder Method 1b. of Materials and Methods {circle around (5)} high ATPCDK2: CDK2/CycE1 kinase assay as described under Method 2b. of Materialsand Methods

TABLE 3 Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460,DU145, Caco-2, B16F10 and A2780 cells by compounds according to thepresent invention, determined as described under Method 3. of Materialsand Methods. {circle around (1)} Structure {circle around (2)} {circlearound (3)} {circle around (4)} {circle around (5)} {circle around (6)}{circle around (7)} {circle around (8)} {circle around (9)} 1

101 212 317 195 341 289 65 n.t. 2

76 54 95 75 91 101 n.t. n.t. 3

24 33 55 34 52 34 14 18 All IC₅₀ (inhibitory concentration at 50% ofmaximal effect) values are indicated in nM, “n.t.” means that thecompounds have not been tested in this assay. {circle around (1)}Example Number {circle around (2)} Inhibition of HeLa cell proliferation{circle around (3)} Inhibition of HeLa-MaTu-ADR cell proliferation{circle around (4)} Inhibition of NCI-H460 cell proliferation {circlearound (5)} Inhibition of DU145 cell proliferation {circle around (6)}Inhibition of Caco-2 cell proliferation {circle around (7)}: Inhibitionof B16F10 cell proliferation {circle around (8)}: Inhibition of A2780cell proliferation {circle around (9)}: Inhibition of MOLM13 cellproliferation

TABLE 4 Caco-2 permeation of compounds according to the presentinvention, determined as described under Method 4, of Materials andMethod. {circle around (1)} Structure {circle around (2)} {circle around(3)} {circle around (4)} {circle around (5)} 1

2 178 191 1.1 {circle around (1)} Example Number {circle around (2)}Concentration of test compound indicated in μM. {circle around (3)}P_(app) A-B (M_(ari)) indicated in [nm/s] {circle around (4)} P_(app)B-A (M_(ari)) indicated in [nm/s] {circle around (5)} Efflux ratio

The invention claimed is:
 1. A compound of general formula (I)

wherein R¹ represents a group selected from C₁-C₆-alkyl-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,phenyl-C₁-C₃-alkyl- or heteroaryl-C₁-C₃-alkyl-, wherein said group isoptionally substituted with one or two or three substituents,identically or differently, selected from the group of hydroxy, cyano,halogen, halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, —OP(O)(OH)₂, —C(O)OH, —C(O)NH₂; R² represents a groupselected from

R³ , R⁴ represent, independently from each other, a group selected froma hydrogen atom, fluoro atom, chloro atom, bromo atom, cyano,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; R⁵represents a group selected from a) a C₁-C₆-alkyl group, which isoptionally substituted with one or two or three substituents,identically or differently, selected from halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, wherein saidC₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from halogen, hydroxy, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-; b) a C₃-C₇-cycloalkyl- group, which is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, hydroxy, —NH₂,alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-, C₂-C₃-alkynyl-; c) aheterocyclyl- group, which is optionally substituted with one or two orthree substituents, identically or differently, selected from the groupof halogen, hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-, C₂-C₃-alkenyl-,C₂-C₃-alkynyl-; d) a phenyl group, which is optionally substituted withone or two or three substituents, identically or differently, selectedfrom the group of halogen, hydroxy, —NH₂, alkylamino-, dialkylamino-,acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; e)a heteroaryl group, which is optionally substituted with one or two orthree substituents, identically or differently, selected from the groupof halogen, hydroxy, —NH₂, alkylamino-, dialkylamino-, acetylamino-,N-methyl-N-acetylamino-, cyclic amines, cyano, C₁-C₃-alkyl-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; f) aphenyl-C₁-C₃-alkyl- group, which phenyl group is optionally substitutedwith one or two or three substituents, identically or differently,selected from the group of halogen, hydroxy, —NH₂, alkylamino-,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-; g) a heteroaryl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,—NH₂, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,cyclic amines, cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; h) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl-group, which C₃-C₆-cycloalkyl group is optionally substituted with oneor two or three substituents, identically or differently, selected fromhalogen, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-; i) a heterocyclyl-C₁-C₃-alkyl- group, whichheterocyclyl group is optionally substituted with one or two or threesubstituents, identically or differently, selected from halogen,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; R⁶,R⁷ represent, independently from each other, a group selected from ahydrogen atom, fluoro atom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; or its salts, solvates or saltsof solvates.
 2. The compound of general formula (I) according to claim1, wherein R¹ represents a group selected from C₁-C₆-alkyl-,C₃-₅-cycloalkyl-, wherein said group is optionally substituted with onesubstituent selected from the group of hydroxy, C₁-C₃-alkoxy-,halo-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, —NH₂, —OP(O)(OH)₂, —C(O)OH,—C(O)NH₂; R² represents a group selected from

R³ represents a hydrogen atom, a fluoro atom, a chloro atom, C₁-C₃-alkylor halo-C₁-C₃-alkyl-; R⁴ represents a hydrogen atom or a fluoro atom; R⁵represents a group selected from a) a C₁-C₆-alkyl group, which isoptionally substituted with one or two or three substituents,identically or differently, selected from halogen, hydroxy,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,wherein said C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl or heteroarylgroup is optionally substituted with one, two or three substituents,identically or differently, selected from halogen, hydroxy,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-, acetylamino-,N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-; b) a phenyl-C₁-C₃-alkyl- group, which phenyl groupis optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-; c) a heteroaryl-C₁-C₃-alkyl- group, which heteroarylgroup is optionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, hydroxy,dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines,cyano, C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-,C₁-C₃-alkoxy-; d) a C₃-C₆-cycloalkyl-C₁-C₃-alkyl- group, whichC₃-C₆-cycloalkyl group is optionally substituted with one or two orthree substituents, identically or differently, selected from halogen,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; e)a heterocyclyl-C₁-C₃-alkyl- group, which heterocyclyl group isoptionally substituted with one or two or three substituents,identically or differently, selected from halogen, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; R⁶, R⁷ represent,independently from each other, a group selected from a hydrogen atom,fluoro atom, chloro atom, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-; or its salts, solvates or saltsof solvates.
 3. The compound of general formula (I) according to claim1, wherein R¹ represents a C₁-C₆-alkyl group, wherein said group isoptionally substituted with one substituent selected from the group ofhydroxy, C₁-C₃-alkoxy-, —NH₂, —OP(O)(OH)₂; R² represents a groupselected from

R³ represents a hydrogen atom, fluoro atom, C₁-C₂-alkyl orfluoro-C₁-C₂-alkyl-; R⁴ represents a hydrogen atom or a fluoro atom; R⁵represents a group selected from a) a C₁-C₃-alkyl group, which isoptionally substituted with one or two or three substituents,identically or differently, selected from halogen, halo-C₁-C₃-alkyl-; b)a phenyl-C₁-C₃-alkyl- group, which phenyl group is optionallysubstituted with one or two or three substituents, identically ordifferently, selected from the group of halogen, cyano, C₁-C₃-alkyl-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; c) aheteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is optionallysubstituted with one or two substituents, identically or differently,selected from the group of halogen, cyano, C₁-C₃-alkyl-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; R⁶, R₇ represent,independently from each other, a group selected from a hydrogen atom, afluoro atom or a chloro atom; or its salts, solvates or salts ofsolvates.
 4. The compound of general formula (I) according to claim 1,wherein R¹ represents a C₁-C₆-alkyl group, wherein said group isoptionally substituted with one substituent selected from the group ofhydroxy, C₁-C₆-alkoxy-, —NH₂, —OP(O)(OH)₂; R² represents a groupselected from

R³ represents a hydrogen atom, fluoro atom or chloro atom; R⁴ representsa hydrogen atom or a fluoro atom; R⁵ represents a group selected from a)a C₁-C₃-alkyl group, which is optionally substituted with one or two orthree substituents, identically or differently, selected from halogen,halo-C₁-C₃-alkyl-; b) a phenyl-C₁-C₃-alkyl- group, which phenyl group isoptionally substituted with one or two or three substituents,identically or differently, selected from the group of halogen, cyano,C₁-C₃-alkyl-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; c)a heteroaryl-C₁-C₃-alkyl- group, which heteroaryl group is optionallysubstituted with one or two substituents, identically or differently,selected from the group of halogen, cyano, C₁-C₃-alkyl-,halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, C₁-C₃-alkoxy-; R⁶, R⁷ represent,independently from each other, a group selected from a hydrogen atom, afluoro atom or a chloro atom; or its salts, solvates or salts ofsolvates.
 5. The compound of general formula (I) according to claim 1,wherein R³ represents a hydrogen atom, a fluoro atom, a methyl ortrifluoromethyl group; or its salts, solvates or salts of solvates. 6.The compound of general formula (I) according to claim 1, wherein R¹represents a C₁-C₃-alkyl group; R² represents the group

R³ represents a hydrogen atom, a fluoro atom, a methyl or atrifluoromethyl group; R⁴ represents a hydrogen atom; R⁵ represents aC₁-C₃-alkyl group; R⁶ represents fluoro; R⁷ represents hydrogen; or itssalts, solvates or salts of solvates.
 7. The compound according to claim1, which is6-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine6-(4-Fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amine6-(4-Fluoro-2-methoxyphenyl)-N-{4-[(methylsulfonyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyrimidin-4-amine6-(4-Fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(methylsulfonyl)methyl]pyridin-2-yl}pyrimidin-4-amineor its salts, solvates or salts of solvates.
 8. A method for thetreatment of lung carcinomas, prostate carcinomas, cervical carcinomas,colorectal carcinomas, melanomas, or ovarian carcinomas comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of general formula (I) according to claim
 1. 9. Apharmaceutical combination comprising a compound according to claim 1 incombination with at least one or more further active ingredients.
 10. Apharmaceutical composition comprising a compound according to claim 1 incombination with an inert, nontoxic, pharmaceutically suitable adjuvant.11. A method for the preparation of the compounds of formula (I)according to claim 1, in which method a compound of formula (5)

in which R¹, R², R³ and R⁴ are as defined according to claim 1, isoxidized with an alkali salt of permanganic acid in an aliphatic ketoneof the formula C₁-C₂-alkyl-C(═O)—C₁-C₂-alkyl as a solvent, thusproviding a compound of general formula (I), according to claim 1, andin which method the resulting compound of formula (I) is optionally, ifappropriate, reacted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the salts ofthe compounds of formula (I).
 12. A method for the preparation of thecompounds of formula (5), in which R¹, R², R³ and R⁴ are as definedaccording to claim 1 for the compounds of general formula (I), in whichmethod a compound of formula (3)

in which R² is as defined according to claim 1 for the compounds ofgeneral formula (I), is reacted with a pyridin-2-amine of formula (4)

in which R¹, R³ and R⁴ are as defined according to claim 1 for thecompounds of general formula (I), in the presence oftris(dibenzylideneacetone)dipalladium(0) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), an alkalicarbonate as a base, and a cyclic ether as a solvent, to give a compoundof formula (5)

in which R¹, R², R³ and R⁴ are as defined according to claim 1 for thecompounds of general formula (I), by means of a Palladium-catalyzed C—Ncross-coupling reaction.